Substituted pyrrolo-pyrazole derivatives active as kinase inhibitors

ABSTRACT

Substituted pyrrolo-pyrazole derivatives of formula (I) and pharmaceutically acceptable salts thereof, as defined in the specification, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful in therapy in the treatment of diseases associated with dysregulated protein kinase activity, like cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional of co-pending application havingU.S. Ser. No. 12/096,989, filed on Jun. 11, 2008, which is a '371 ofinternational application having Serial No. PCT/EP2006/069373, thecontents of all of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to certain substituted bicyclic pyrazolecompounds, which modulate the activity of protein kinases. The compoundsof this invention are therefore useful in treating diseases caused bydysregulated protein kinase activity. The present invention alsoprovides methods for preparing these compounds, pharmaceuticalcompositions comprising these compounds, and methods of treatingdiseases utilizing pharmaceutical compositions comprising thesecompounds.

2. Discussion of the Background

The insulin-like growth factor 1 receptor (IGF-1R, IGF1R) is a member ofthe insulin receptor subfamily of receptor tyrosine kinases (RTKs).IGF-1R mature protein consists of two alpha chains, which areextracellular and contain ligand-binding function, and two beta chains,which span the cell membrane and contain the intracellular kinasedomains. This disulphide-linked (alpha/beta)2 heterodimer complex isable to bind and be activated by the ligands insulin-like growthfactor-1 and -2 (IGF-1 and IGF-2), two circulating growth factors whichare believed to mediate many of the effects of Growth Hormone (GH), andwhich have important physiological roles in foetal and post-natal growthand metabolism. Extracellular ligand binding to IGF-1R results inintracellular tyrosine kinase activation, and like several other RTKssuch as the EGF and PDGF receptors, the activated receptor has potentmitogenic, motogenic and anti-apoptotic activity in a wide range of celltypes: notably, it directly activates at least two major cell signallingpathways, the ras/MAPK pathway, through recruitment of SHC, and the PI-3kinase/AKT(PKB) pathway, through recruitment and phosphorylation of theIRS adapter proteins. There is much evidence, both at preclinical andclinical levels, linking increased IGF-1R signalling to development andprogression of cancer. This evidence includes observation that IGF-1R isable to induce cellular transformation, that fibroblasts from animalslacking IGF-1R through genetic ablation are extremely resistant to thetransforming activity of a wide range of oncogenes, and that IGFs arepotent anti-apoptotic agents. Studies of interference with receptoractivity through various approaches have demonstrated that inhibition ofIGF-1R dependent signalling can result in single agent antitumoractivity, and in the enhancement of the activity of a wide range ofchemotherapeutic agents and radiotherapy in human tumor cells culturedin vitro, as well as in animal models of disease, including human tumorxenograft models. Such IGF-1R inhibition strategies have includedcellular transfection with dominant negative IGF-1R constructs orantisense oligonucleotides, use of IGF binding antagonists and blockingmonoclonal antibodies directed against the extracellular receptor, and,significantly, selective small molecule inhibitors of IGF-1R kinaseactivity. Additional indication that IGF-1R signalling contributes todevelopment of cancer, and thus that inhibition of this receptor mayrepresent a valuable therapeutic option, is provided by the observationthat high circulating levels of IGF-1 in human are associated withincreased lifetime risk of developing several tumor types, includingbreast, colorectal, prostate and ovarian cancers, and with poor outcomein multiple myeloma. Importantly, gene and protein expression studiesperformed on clinical samples have revealed that IGF-1R and its ligandsare frequently expressed in a wide range of human tumors. For anoverview of IGFs and IGF-1R signalling, physiological function, anddetailed description of the evidence supporting involvement of thissystem in human cancer that is summarised above, as well as in otherpathologies, the reader is directed to the many reviews on the subjectand references contained therein, for example Baserga R., Bongo A.,Rubini M., Prisco M. and Valentinis B. Biochim Biophys Acta vol. 1332pages F105-F126, 1997; Khandwala H. M., McCutcheon I. E., Flyvbjerg A.and Friend K. E. Endocr Rev vol. 21, pages 215-44, 2000; Le Roith D.,Bondy C., Yakar S., Liu J. L. and Butler A. Endocr Rev. vol. 22, pages53-74, 2001; Valentinis B., and Baserga R. Mol. Pathol. vol. 54, pages133-7, 2001; Wang Y. and Sun Y., Curr Cancer Drug Targets vol. 2 pages191-207, 2002, Laron, Z. J Clin Endocrinol Metab vol. 89, pages1031-1044, 2004; Hofmann F and Garcia-Echeverria C. Drug Discov Todayvol. 10, pages 1041-7, 2005.

SUMMARY OF THE INVENTION

It has been found that compounds of formula (I), described below, areinhibitors of the tyrosine kinase activity of the IGF-1 receptor.

Accordingly, a first object of the present invention is to provide asubstituted bicyclic pyrrolo[3,4-c]pyrazole compound represented byformula (I),

wherein:

-   R is an optionally further substituted straight or branched C₁-C₆    alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl or aryl;-   R1 is selected from halogen, nitro, NHCOR4, NHSO₂R10, NR5R6, OR7,    R8R9N—C₁-C₆ alkyl, R7O—C₁-C₆ alkyl and an optionally further    substituted straight or branched C₁-C₆ alkyl, wherein:    -   R4 is selected from hydrogen, an optionally further substituted        straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,        heterocycloalkyl, aryl, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆        alkyl;    -   R5 and R6, being the same or different, are independently        selected from hydrogen, an optionally further substituted        straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,        heterocycloalkyl, aryl, R8R9N—C₂-C₆ alkyl and R7O—C₂-C₆ alkyl;    -   R7 is selected from hydrogen, an optionally further substituted        straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,        heterocycloalkyl, aryl and R8R9N—C₂-C₆ alkyl;    -   R8 and R9, being the same or different, are independently        selected from hydrogen, an optionally further substituted        straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,        heterocycloalkyl and aryl, or R8 and R9, taken together with the        nitrogen atom to which they are bonded, form an optionally        substituted heterocycloalkyl group;    -   R10 is an optionally further substituted straight or branched        C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl or aryl;-   A, B, D and E represent a nitrogen atom, CH, CR2 or CR3, with a    maximum of two of A, B, D and E representing a nitrogen atom, and    with a maximum of two of A, B, D and E representing CR2 or CR3,    wherein:    -   R2 and R3, being the same or different, are independently        selected from halogen, trifluoromethyl, nitro, OR7, NR8R9, an        optionally further substituted straight or branched C₁-C₆ alkyl,        R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl, wherein R7, R8, and R9        are as defined above;-   Ra and Rb, being the same or different, are selected from hydrogen    or methyl, with the provisos that:-   when Ra and Rb are hydrogen atoms, and each of A, B, D and E are CH,    CR2 or CR3, then R1 is not OH, OCH₃, Cl, F or CH₃; and-   when A, D and E are CH, and B is CR2, wherein R2 is    4-methylpiperazine or morpholine, then R1 is not trifluoromethyl, F,    nitro, amino, NHCOR4^(I) wherein R4^(I) is isopropyl [—CH(CH₃)₂],    cyclobutyl, —CH₂NHCH₃, —CH₂N(CH₃)₂, —CH(NH₂)CH₃ or pyrrolidin-2-yl;-   or isomers, tautomers, carriers, metabolite, prodrugs and    pharmaceutically acceptable salt thereof.

The present invention also provides a method for treating diseasescaused by and/or associated with dysregulated protein kinase activity,particularly IGF-1R or Aurora kinases activity, and more particularlyIGF-1R kinase activity, which comprises administering to a mammal inneed thereof an effective amount of a substituted pyrrolo pyrazolecompound represented by formula (I) as above defined.

A preferred method of the present invention is to treat a disease causedby and/or associated with dysregulated protein kinase activity selectedfrom the group consisting of cancer, cell proliferative disorders, viralinfections, retinopathies including diabetic and neonatal retinopathiesand age related macular degeneration, atherosclerosis and conditionsinvolving vascular smooth muscle proliferation or neointimal formationsuch as restenosis following angioplasty or surgery, graft vesseldisease, such as can occur following vessel or organ transplantation,acromegaly and disorders secondary to acromegaly as well as otherhypertrophic conditions in which IGF/IGF-1R signalling is implicated,such as benign prostatic hyperplasia, psoriasis, fibrotic lung disease,pulmonary fibrosis, pathologies related to chronic or acute oxidativestress or hyperoxia induced tissue damage, and metabolic disorders inwhich elevated IGF levels or IGF-1R activity are implicated, such asobesity.

Another preferred method of the present invention is to treat specifictypes of cancer including carcinoma, squamous cell carcinoma,hematopoietic tumors of myeloid or lymphoid lineage, tumors ofmesenchymal origin, tumors of the central and peripheral nervous system,melanoma, seminoma, teratocarcinoma, osteosarcoma, xerodermapigmentosum, keratocanthomas, thyroid follicular cancer and Kaposi'ssarcoma. Another preferred method of the present invention is to treatspecific types of cancer such as, but not restricted to, breast cancer,lung cancer, colorectal cancer, prostate cancer, ovarian cancer,endometrial cancer, gastric cancer, clear cell renal cell carcinoma,uveal melanoma, multiple myeloma, rhabdomyosarcoma, Ewing's sarcoma,Kaposi' sarcoma, and medulloblastoma.

Another preferred method of the present invention is to treat cellproliferative disorders such as, but not restricted to, benign prostatehyperplasia, familial adenomatosis polyposis, neuro-fibromatosis,psoriasis, vascular smooth cell proliferation associated withatherosclerosis, pulmonary fibrosis, arthritis, glomerulonephritis andpost-surgical stenosis and restenosis.

In addition, the method of the present invention also provides tumorangiogenesis and metastasis inhibition.

The present invention also provides methods of synthetizing thesubstituted pyrrolo pyrazole derivatives of formula (I) prepared througha process consisting of standard synthetic transformations.

The present invention also provides a pharmaceutical compositioncomprising one or more compounds of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable excipient,carrier or diluent.

The present invention further provides a pharmaceutical compositioncomprising a compound of formula (I) in combination with one or morechemotherapeutic agents or radiotherapy. Such agents can include, butare not limited to, antihormonal agents such as antiestrogens,antiandrogens and aromatase inhibitors, topoisomerase I inhibitors,topoisomerase II inhibitors, agents that target microtubules,platin-based agents, alkylating agents, DNA damaging or intercalatingagents, antineoplastic antimetabolites, other kinase inhibitors, otheranti-angiogenic agents, inhibitors of kinesins, therapeutic monoclonalantibodies, inhibitors of mTOR, histone deacetylase inhibitors, farnesyltransferase inhibitors, and inhibitors of hypoxic response.

DETAILED DESCRIPTION OF THE INVENTION

Several fused bicyclic compounds comprising pyrazole moieties andpossessing kinase inhibitory activity have been disclosed in WO00/69846, WO 02/12242, WO 03/028720, WO 03/097610, WO 04/007504, WO04/013146, US2005/0026984 and WO 2005030776. The compounds of formula(I) may have one or more asymmetric centres, and may therefore exist asindividual optical isomers or racemic mixtures. Accordingly, all thepossible isomers, and their mixtures, of the compounds of formula (I)are within the scope of the present invention.

Derivatives of compounds of formula (I) originating from metabolism in amammal, and the pharmaceutically acceptable bio-precursors (otherwisereferred to as pro-drugs) of the compounds of formula (I) are alsowithin the scope of the present invention.

In addition to the above, as known to those skilled in the art, theunsubstituted nitrogen on the pyrazole ring of the compounds of formula(I) rapidly equilibrates in solution to form a mixture of tautomers, asdepicted below:

wherein R, R1, Ra and Rb, and A, B, D, E are as defined above.

Accordingly, in the present invention, where only one tautomer isindicated for the compounds of formula (I), the other tautomer (Ia) isalso within the scope of the present invention, unless specificallynoted otherwise.

In compounds of formula (I), the skilled person will recognize that themeaning of A, B, D, and E is such that the resulting six-membered ringlinked to the aminopyrazole group through an amidic bond is an aromaticring, optionally substituted by up to three substituents. Representativeand not limiting examples of ring systems are the following:

The general terms as used herein, unless otherwise specified, have themeaning reported below.

The term “straight or branched C₁-C₆ alkyl” refers to a saturatedaliphatic hydrocarbon radical, including straight chain and branchedchain groups of from 1 to 6 carbon atoms, e.g. methyl, ethyl, propyl,2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and the like. The alkylgroup may be substituted or unsubstituted. When substituted, thesubstituent groups are preferably one to three, independently selectedfrom the group consisting of halogen, trifluoromethyl, alkylthio, cyano,nitro, formyl, alkylcarbonyl, alkylsulfonyl, carboxy, carboxamido,monoalkylcarboxamido, dialkylcarboxamido, hydroxyalkyl, OR7, NR8R9, arylor arylalkyl, wherein R7, R8 and R9 are as defined above.

The term “C₃-C₆ cycloalkyl” refers to a 3- to 6-membered all-carbonmonocyclic ring, which may contain one or more double bonds but does nothave a completely conjugated π-electron system. Examples of cycloalkylgroups, without limitation, are cyclopropane, cyclobutane, cyclopentane,cyclopentene, cyclohexane, cyclohexene and cyclohexadiene. A cycloalkylgroup may be substituted or unsubstituted. When sustituted, thesubstituent groups are preferably one or two substituents, independentlyselected from the group consisting of halogen, trifluoromethyl,alkylthio, cyano, nitro, formyl, alkylcarbonyl, alkylsulfonyl, carboxy,carboxamido, monoalkylcarboxamido, dialkylcarboxamido, hydroxyalkyl,OR7, NR8R9, aryl and arylalkyl, wherein R7, R8 and R9 are as definedabove.

The term “heterocycloalkyl” refers to a 3- to 7-membered, saturated orpartially unsaturated carbocyclic ring where one or more carbon atomsare replaced by heteroatoms such as nitrogen, oxygen and sulfur. Notlimiting examples of heterocycloalkyl groups are, for instance, oxirane,aziridine, oxetane, azetidine, tetrahydrofuran, dihydrofuran,tetrahydrothiophene, dihydrothiophene, pyrrolidine, dihydropyrrole,pyran, dihydropyran, tetrahydropyran, tetrahydrothiopyran, piperidine,pyrazoline, isoxazolidine, isoxazoline, thiazolidine, thiazoline,isothiazoline, dioxane, piperazine, morpholine, thiomorpholine,examethyleneimine, homopiperazine and the like. An heterocycloalkylgroup may be substituted or unsubstituted. When substituted, thesubstituent groups are preferably one or two substituents, independentlyselected from the group consisting of halogen, trifluoromethyl,alkylthio, cyano, nitro, formyl, alkylcarbonyl, alkylsulfonyl, carboxy,carboxamido, monoalkylcarboxamido, dialkylcarboxamido, hydroxyalkyl,OR7, NR8R9, aryl and arylalkyl, wherein R7, R8 and R9 are as definedabove.

The term “aryl” refers to a mono-, bi- or poly-carbocyclic as well asheterocyclic hydrocarbon with from 1 to 4 ring systems, either fused orlinked to each other by single bonds, wherein at least one of thecarbocyclic or heterocyclic rings is aromatic. Not limiting examples ofaryl groups are, for instance, phenyl, α- or β-naphthyl,9,10-dihydroanthracenyl, indanyl, fluorenyl, biphenyl, pyrrolyl, furoyl,thiophenyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, indolyl, benzofuranyl, benzothiophenyl, benzimidazolyl,benzopyrazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl,benzoisothiazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl and the like.

The term “aryl” may also refer to aromatic carbocyclic or heterocyclicrings further fused or linked to non-aromatic heterocyclic rings,typically 5- to 7-membered heterocycles. Not limiting examples of sucharyl groups are, for instance, 2,3-dihydroindolyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothiophenyl; benzopyranyl,2,3-dihydrobenzoxazinyl, 2,3-dihydroquinoxalinyl and the like.

The aryl group can be optionally substituted by one to three, preferablyone or two, substituents selected from an optionally further substitutedstraight or branched C₁-C₆ alkyl, halogen, trifluoromethyl, alkylthio,cyano, nitro, formyl, alkylcarbonyl, alkylsulfonyl, carboxy,carboxamido, monoalkylcarboxamido, dialkylcarboxamido, hydroxyalkyl, OR7and NR8R9, wherein R7, R8 and R9 are as defined above.

The term “halogen” indicates fluorine, chlorine, bromine or iodine.

The term “trifluoromethyl” indicates a —CF₃ group.

The term “hydroxyalkyl” indicates a hydroxy group linked to an alkylgroup. Examples of hydroxyalkyl groups are hydroxymethyl (—CH₂OH),hydroxyethyl (—CH₂CH₂OH) and the like.

The term “alkylthio” indicates an alkyl group linked to a sulphur atom(—S-alkyl). Examples of alkylhio groups are methylthio (—SCH₃),ethylthio (—SCH₂CH₃), isopropylthio [—SCH(CH₃)₂] and the like.

The term “alkylcarbonyl” indicates an alkyl residue linked to a CO group[—C(═O)alkyl]. Examples of alkylcarbonyl are methylcarbonyl [—C(═O)CH₃],ethylcarbonyl [—C(═O)CH₂CH₃] and the like.

The term “alkylsulfonyl” indicates a —SO₂alkyl group. Examples ofalkylsulfonyl groups are methylsulfonyl (—SO₂CH₃), ethylsulfonyl(—SO₂CH₂CH₃) and the like.

The term “arylalkyl” indicates an aryl group linked to a C₁-C₄ alkylchain. Examples of aryalkyl are benzyl (—CH₂Ph), phenetyl (—CH₂CH₂Ph)and the like.

The terms “monoalkylcarboxamido” or “dialkylcarboxamido” indicate acarboxamido group where one or both hydrogens are substituted by analkyl group. Examples of monoalkylcarboxamido are methylcarboxamido(—CONHCH₃), ethylcarboxamido (—CONHCH₂CH₃), and the like. Examples ofdialkylcarboxamido are dimethylcarboxamido [—CON(CH₃)₂],diethylcarboxamido [—CON(CH₂CH₃)₂] and the like.

The term “pharmaceutically acceptable salt” of compounds of formula (I)refers to those salts that retain the biological effectiveness andproperties of the parent compounds.

Such salts include:

-   acid addition salt with inorganic acids such as hydrochloric,    hydrobromic, nitric, phosphoric, sulfuric, perchloric acid and the    like, or with organic acids such as acetic, trifluoroacetic,    propionic, glycolic, lactic, (D) or (L) malic, maleic,    methanesulfonic, ethanesulfonic, benzoic, p-toluenesulfonic,    salicylic, cinnamic, mandelic, tartaric, citric, succinic, malonic    acid and the like;-   salts formed when an acidic proton present in a compound of    formula (I) is either replaced by a metal ion, e.g., an alkali metal    ion such as sodium or potassium, or an alkaline earth ion such as    calcium or magnesium, or coordinates with an organic base such as    ethanolamine, diethanolamine, triethanolamine, tromethamine,    N-methylglucamine, and the like.

Preferred compounds of formula (I) are the compounds wherein:

-   R is selected from C₃-C₆ cycloalkyl, heterocycloalkyl and aryl;-   R1 is selected from halogen, NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl,    R7O—C₁-C₆ alkyl and an optionally further substituted straight or    branched C₁-C₆ alkyl;-   A and D are CH or nitrogen, B is nitrogen, CH or CR2, and E is CH or    CR3;-   R2 and R3 are independently selected from halogen, trifluoromethyl,    OR7, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl.

Other preferred compounds of formula (I) are the compounds wherein:

-   R is selected from C₃-C₆ cycloalkyl, heterocycloalkyl and aryl;-   R1 is selected from NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl, R7O—C₁-C₆    alkyl and an optionally further substituted straight or branched    C₁-C₆ alkyl;-   A is CH or nitrogen, B is nitrogen, CH or CR2, E is CH or CR3, and D    is CH;-   R2 and R3 are independently selected from halogen, OR7, NR8R9,    R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl.

Further preferred compounds of formula (I) are the compounds wherein:

-   R is heterocycloalkyl or aryl;-   R1 is selected from NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl and an    optionally further substituted straight or branched C₁-C₆ alkyl;-   B is CH or CR2, E is CH or CR3, and A and D are CH;-   R2 and R3 are independently selected from halogen, OR7, NR8R9,    R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl;-   Ra and Rb are methyl.

Particularly preferred compounds of formula (I) are the compoundswherein:

-   R is aryl;-   R1 is selected from NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl and an    optionally further substituted straight or branched C₁-C₆ alkyl;-   B and E are CH, CR2 or CR3, and A and D are CH;-   R2 and R3 are independently selected from halogen, OR7, NR8R9,    R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkyl;-   Ra and Rb are methyl.

Most preferred compounds of formula (I) are the compounds wherein:

-   R is aryl;-   R1 is selected from NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl and an    optionally further substituted straight or branched C₁-C₆ alkyl;-   B is CR2, and A, D and E are CH;-   R2 is selected from OR7, NR8R9, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆    alkyl; Ra and Rb are methyl.

Specific compounds (cpd.) of the invention are listed below:

-   1. (S)-Tetrahydro-furan-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   2. (R)-Tetrahydro-furan-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   3. Piperidine-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   4. Piperidine-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   5. Piperidine-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   6. Tetrahydro-furan-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   7. Tetrahydro-pyran-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   8. Tetrahydro-pyran-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   9. Tetrahydro-pyran-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   10. 1H-Pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   11. 1H-Pyrrole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   12. 1-Methyl-1H-pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   13. 1-Methyl-1H-pyrrole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   14. 3H-Imidazole-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   15. 3-Methyl-3H-imidazole-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   16. 1-Methyl-1H-imidazole-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   17. 1H-Imidazole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   18. 1-Methyl-1H-imidazole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   19. Pyridine-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   20.    N-[2-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-nicotinamide;-   21.    N-[2-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-isonicotinamide;-   22.    2-Benzoylamino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;-   23. 5-Methyl-isoxazole-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   24. Thiophene-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   25. Thiophene-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   26. Furan-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   27. Furan-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   28. 2H-Pyrazole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   29. 2-Methyl-2H-pyrazole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   30. 1-Methyl-1H-pyrazole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   31. 5-Methyl-2H-pyrazole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   32. 1H-Pyrazole-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   33. 1-Methyl-1H-pyrazole-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   34. Thiazole-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   35. 3-Methyl-thiophene-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   36. 1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;-   37. 1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;-   38. 1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide;-   39. 1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-fluoro-phenyl}-amide;-   40. 1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide;-   41. 1H-Pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-dimethylamino-ethoxy)-phenyl]-amide;-   42. 1H-Pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide;-   43. 1H-Pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-azetidin-3-yloxy)-phenyl]-amide;-   44. 1H-Pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-piperidin-4-yloxy)-phenyl]-amide;-   45. 1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-amide;-   46. 1H-Pyrrole-3-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;-   47. 1H-Pyrrole-3-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;-   48. 1H-Pyrrole-3-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide;-   49. 1H-Pyrrole-3-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-amide;-   50. 1H-Pyrrole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-dimethylamino-ethoxy)-phenyl]-amide;-   51. 1H-Pyrrole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-azetidin-3-yloxy)-phenyl]-amide;-   52. 1H-Pyrrole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-piperidin-4-yloxy)-phenyl]-amide;-   53. 1H-Pyrrole-3-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide;-   54. 1H-Pyrrole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide;-   55. (S)-1-Methyl-pyrrolidine-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;-   56. (S)-1-Methyl-pyrrolidine-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide;-   57. 1H-Imidazole-4-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;-   58. 1-Methyl-1H-pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;-   59. 1-Methyl-1H-pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide;-   60. 1-Methyl-1H-pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;-   61. 1-Methyl-1H-pyrrole-2-carboxylic acid [2-[5-(3,5-difluoro-benz    enesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-dimethylamino-ethoxy)-phenyl]-amide;-   62. 1-Methyl-1H-pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide;-   63. 1-Methyl-1H-pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-azetidin-3-yloxy)-phenyl]-amide;-   64. 1-Methyl-1H-pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-piperidin-4-yloxy)-phenyl]-amide;-   65. 1-Methyl-1H-pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-amide;-   66. 1-Methyl-1H-pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide;-   67.    2-[(3-Pyrrolidin-1-ylmethyl-benzoyl)amino]-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide;-   68. Tetrahydro-pyran-4-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;-   69. Tetrahydro-pyran-4-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;-   70. Tetrahydro-pyran-4-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide;-   71. Tetrahydro-pyran-4-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-[(2-dimethylamino-ethyl)-methyl-amino]-phenyl}-amide;-   72. Tetrahydro-pyran-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(2-dimethylamino-ethoxy)-phenyl]-amide;-   73. Tetrahydro-pyran-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-azetidin-3-yloxy)-phenyl]-amide;-   74. Tetrahydro-pyran-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(1-methyl-piperidin-4-yloxy)-phenyl]-amide;-   75. Pyridine-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;-   76.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[((S)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide;-   77.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-[(((R)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide;-   78.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   79.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-dimethylamino-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   80.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   81.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-methoxy-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   82.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(2-dimethylamino-ethoxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   83.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(2-pyrrolidin-1-yl-ethoxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   84.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(1-methyl-azetidin-3-yloxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   85.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(1-methyl-piperidin-4-yloxy)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   86.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-[(2-dimethylamino-ethyl)-methyl-amino]-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   87.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino]-4-morpholin-4-yl-benzamide;-   88.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(piperidin-3-ylmethyl)-amino]-benzamide;-   89.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-phenylamino-benzamide;-   90.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-isobutylamino-4-(4-methyl-piperazin-1-yl)-benzamide;-   91.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((R)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide;-   92.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((S)-1-pyrrolidin-2-ylmethyl)-amino]-benzamide;-   93.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(furan-2-ylmethyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzamide;-   94.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(1H-imidazol-2-ylmethyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzamide;-   95.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   96.    2-Benzylamino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide;-   97.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-thiopyran-4-ylamino)-benzamide;-   98.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(piperidin-4-ylamino)-benzamide;-   99.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-hydroxy-b    enzylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   100.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino]-benzamide;-   101.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-hydroxy-b    enzylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   102. 1H-Pyrrole-2-carboxylic acid    [2-(5-benzenesulfonyl-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl)-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   103. 1H-Pyrrole-2-carboxylic acid    [2-[5-(3-fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   104.    N-[5-(3-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   105. 1-Methyl-1H-pyrrole-2-carboxylic acid    [2-[5-(3-fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   106. 1H-Pyrrole-3-carboxylic acid    [2-[5-(3-fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   107. Tetrahydro-pyran-4-carboxylic acid    [2-[5-(3-fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   108. Tetrahydro-furan-2-carboxylic acid    [2-[5-(3-fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   109.    N-[5-(2-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   110.    N-[5-(3,5-Dichloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   111.    N-[5-(3-Chloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   112.    N-[6,6-Dimethyl-5-(thiophene-2-sulfonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   113.    N-[5-(2,6-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   114.    N-[6,6-Dimethyl-5-(pyridine-3-sulfonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   115. N-[5-(3-Methoxy-benz    enesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   116.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-3-[(1H-pyrrole-2-carbonyl)-amino]-isonicotinamide;-   117.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-3-(tetrahydro-pyran-4-ylamino)-isonicotinamide;-   118.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-hydroxy-cyclohexylamino)-nicotinamide;-   119.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-nicotinamide;-   120.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(1H-pyrrole-2-carbonyl)-amino]-nicotinamide;-   121. 3-(Tetrahydro-pyran-4-ylamino)-pyridine-2-carboxylic acid    [5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide;-   122. 3-[(1H-Pyrrole-2-carbonyl)-amino]-pyridine-2-carboxylic acid    [5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide;-   123. 1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-3-fluoro-phenyl}-amide;-   124.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-(tetrahydro-pyran-4-ylamino)-benzamide;-   125. 1H-Pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-3-fluoro-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   126.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-4-(4-methyl-piperazin-1-yl)-6-(tetrahydro-pyran-4-ylamino)-benzamide;-   127.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-ethyl-ureido)-4-(4-methyl-piperazin-1-yl)-benzamide;-   128.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3,3-dimethyl-ureido)-4-(4-methyl-piperazin-1-yl)-benzamide;-   129. Pyrrolidine-1-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   130. Morpholine-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   131. 1H-Pyrrole-2-carboxylic acid    [2-(5-benzenesulfonyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl)-phenyl]-amide;-   132.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-dimethylaminomethyl-6-fluoro-benz    amide;-   133.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-(isopropylamino-methyl)-benzamide;-   134.    2-Cyclopentylaminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-6-fluoro-benzamide;-   135.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-[(tetrahydro-pyran-4-ylamino)-methyl]-benzamide;-   136.    2-Cyclobutylaminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-6-fluoro-benzamide;-   137.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-morpholin-4-ylmethyl-benzamide;-   138.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-dimethylaminomethyl-benzamide;-   139.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(isopropylamino-methyl)-benzamide;-   140.    2-Cyclopentylaminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide;-   141.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(tetrahydro-pyran-4-ylamino)-methyl]-benzamide;-   142.    2-Cyclobutylaminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide;-   143.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-morpholin-4-ylmethyl-benz    amide;-   144. Tetrahydro-furan-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   145.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-dimethylamino-acetylamino)-benzamide;-   146.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methylamino-acetylamino)-benzamide;-   147. (S)-Pyrrolidine-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;-   148. (S)-Pyrrolidine-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide;-   149.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(tetrahydro-furan-2-ylmethyl)-amino]-nicotinamide;-   150.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-hydroxy-propylamino)-nicotinamide;-   151.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-methoxy-benzylamino)-nicotinamide;-   152.    2-Chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-nicotinamide;-   153.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-nicotinamide;-   154.    2,6-Dichloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-nicotinamide;-   155.    6-Chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2,4-dimethoxy-benzylamino)-nicotinamide;-   156.    6-Chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2,4-dimethoxy-benzylamino)-nicotinamide;-   157.    6-Chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-nicotinamide;-   158.    2-Amino-6-chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-nicotinamide;-   159.    2-Chloro-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-6-morpholin-4-yl-nicotinamide;-   160.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2,4-dimethoxy-benzylamino)-6-morpholin-4-yl-nicotinamide;-   161.    2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-nicotinamide;-   162.    N-{5-[3-Fluoro-5-(3-hydroxy-propylamino)-benzenesulfonyl]-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl}-2-(3-hydroxy-propylamino)-nicotinamide;-   163.    2-Aminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-6-fluoro-benzamide;-   164.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   165.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   166.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   167.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   168.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methoxy-1-methoxymethyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   169.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-methoxy-1-methyl-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   170.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((R)-3-methoxy-1-methyl-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   171.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((S)-3-methoxy-1-methyl-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide    and-   172.    N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-methoxy-propylamino)-4-(4-methyl-piperazin-1-yl)-benzamide.

Preferred specific compounds (cpd.) of the invention are listed below:

-   (S)-Tetrahydro-furan-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   Tetrahydro-pyran-4-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   1H-Pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   1H-Pyrrole-3-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   1-Methyl-1H-pyrrole-2-carboxylic acid    [2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;-   1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;-   1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;-   1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide;-   1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide;-   1H-Pyrrole-3-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;-   1H-Pyrrole-3-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;-   1-Methyl-1H-pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide;-   Tetrahydro-pyran-4-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;-   Tetrahydro-pyran-4-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide;-   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-dimethylamino-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   1H-Pyrrole-2-carboxylic acid    {2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-3-fluoro-phenyl}-amide;-   N-[5-(3-Chloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   N-[5-(3-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;-   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;-   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide    and-   N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide.

The present invention also provides a process for the preparation of acompound of formula (I) defined as above; which process comprises:

-   a) reacting a compound of formula (II)

wherein Ra and Rb are as defined above, Q is a lower alkyl group, forinstance a C₁-C₄ alkyl group, more preferably methyl or ethyl,with a compound of formula (III)

wherein R1 and A, B, D, E are as defined above and Z is hydroxy, halogenor a suitable leaving group;

-   b) deprotecting the resulting compound of formula (IV),

wherein R1, A, B, D, E, Ra, Rb, and Q are as defined above, under acidicconditions;

-   c) reacting the resulting compound of formula (V),

wherein R1, A, B, D, E, Ra, Rb, and Q are as defined above, with acompound of formula (VI),

wherein Z and R are as defined above so as to obtain a compound offormula (VII),

wherein R, R1, A, B, D, E, Ra, Rb, and Q are as defined above andoptionally converting it into another compound of formula (VII);

-   d) deprotecting the compound of formula (VII) as defined above under    basic conditions so as to obtain the corresponding compound of    formula (I), which can be further separated into the single isomers    when it contains one or more asymmetric centers, and optionally    converting it into another compound of formula (I) and/or into a    pharmaceutically acceptable salt if desired.

It is to be noted that a compound of formula (II), (IV), (V) and (VII)as above defined can be in any one of its isomeric forms a or b:

As said above, a compound of formula (VII) may be converted into anothercompound of formula (VII), the following being examples of possibleconversions:

-   1) preparation of a compound of formula (VII), wherein R1 is amino    by reducing a compound of formula (VII), wherein R1 is nitro;-   2) preparation of a compound of formula (VII), wherein R1 is NHCOR4    by reacting a compound of formula (VII), wherein R1 is amino with a    compound of formula (VIII),

wherein R4 and Z are as defined above;

-   3) preparation of a compound of formula (VII), wherein R1 is    NHCONHR8 by reacting a compound of formula (VII), wherein R1 is    amino with an isocyanate of formula (IX),    R8-N═C═O  (IX)    wherein R8 is as defined above;-   4) preparation of a compound of formula (VII), wherein R1 is    NHSO₂R10, and R, A, B, D, E, Ra, Rb, R10 and Q are as defined above,    reacting a compound of formula (VII),    wherein R1 is amino and R, A, B, D, E, Ra, Rb and Q are as defined    above, with a compound of formula (X),

wherein R10 and Z are as defined above;

-   5) preparation of a compound of formula (VII), wherein R1 is a NR5R6    group, wherein one of the R5 or R6 is hydrogen and the other is an    optionally further substituted straight or branched C₁-C₆ alkyl,    C₃-C₆ cycloalkyl, heterocycloalkyl, R8R9N—C₂-C₆ alkyl, R7O—C₂-C₆    alkyl, wherein R7, R8 and R9 are as defined above, by reacting a    compound of formula (VII), wherein R1 is amino with a suitable    aldehyde or ketone in presence of a reducing agent.

As said above, a compound of formula (I) may be converted into anothercompound of formula (I), the following being an example of possibleconversions:

-   a compound of formula (I), wherein R1 is amino may be converted into    a compound of formula (I) wherein R1 is NR5R6, wherein R5 and R6 are    defined as in conversion 5), by reacting it with a suitable aldeyde    or ketone in presence of a reducing agent.

The synthesis of a compound of formula (I), according to the syntheticprocess described above, can be conducted in a stepwise manner, wherebyeach intermediate is isolated and purified by standard purificationtechniques, like, for example, column chromatography, before carryingout the subsequent reaction. Alternatively, two or more steps of thesynthetic sequence can be carried out in a so-called “one-pot”procedure, as known in the art, whereby only the compound resulting fromthe two or more steps is isolated and purified.

According to step a) of the process, the reaction between a compound offormula (II) and a compound of formula (III) can be carried out in avariety of ways, according to conventional methods for acylating aminoderivatives. As an example, a compound of formula (II) may be reactedwith an acyl chloride of formula (III), in which case Z represents achlorine atom. Preferably, this reaction is carried out in a suitablesolvent such as, for instance, tetrahydrofuran, dichloromethane,toluene, 1,4-dioxane, acetonitrile and in presence of a proton scavengersuch as, for example, triethylamine, N,N-diisopropylethylamine,pyridine, at a temperature ranging from room temperature to reflux, fora time ranging from about 30 min. to about 96 hours. It is known to theskilled person that when a compound of formula (III) carries functionalgroups that may interfere with the above reaction, such groups have tobe protected before carrying out the reaction. In particular, when acompound of formula (III) is substituted by residues of general formulaNR5R6, OR7, or R8R9N—C₁-C₆ alkyl, wherein R7 or one or both of R5 andR6, or R8 and R9 represent hydrogen, such groups are protected as knownin the art. Introduction of a nitrogen protecting group may also berequired for a compound of formula (III), wherein R1 is NHCOR7 orNHSO₂R10. It is also known to the skilled person that such protectinggroup may be removed just after the reaction of a compound of formula(III) with a compound of formula (II) or at a later stage in thesynthetic process. Removal of some protective groups may also affect thepyrazole protecting group (—COOQ) of a compound of formula (IV) or(VII). If needed, such pyrazole protecting group can be reinstalled at alater stage in the synthetic process.

According to step b) of the process, a compound of formula (IV) iseasily deprotected at the dihydropyrrole nitrogen atom by acidictreatment. This reaction can be conveniently carried out in presence ofan inorganic or organic acid such as, for instance, hydrochloric,trifluoroacetic or methanesulfonic acid, in a suitable solvent such asdichloromethane, 1,4-dioxane, a lower alcohol, such as methanol orethanol, at a temperature ranging from room temperature to about 40° C.and for a period of time varying from about 1 hour to about 48 hours.

The compound of formula (V) thus obtained is further reacted, accordingto step c) of the process, with a compound of formula (VI). From theabove it is clear to the skilled person that this sulfonylation reactionmay be accomplished in a variety of ways and experimental conditions,which are widely known in the art for the preparation of sulfonamides.As an example, the reaction between a compound of formula (V) and asulfonyl chloride of formula (VI), in which case Z is a chlorine atom,can be carried out in a suitable solvent such as, for instance, diethylether, tetrahydrofuran, dichloromethane, chloroform, toluene,1,4-dioxane, acetonitrile and in presence of a proton scavenger such as,for instance, triethylamine, N,N-diisopropylethylamine, pyridine, at atemperature ranging from about −10° C. to reflux, and for a period oftime ranging, for instance, from about 30 min to about 96 hours.

According to step d) of the process, a compound of formula (VII) istransformed into a compound of formula (I) by deprotection of thepyrazole nitrogen atom by working according to conventional methodsenabling the selective hydrolysis of a carbamate protecting group. As anexample, this reaction may be carried out under basic conditions, forinstance in presence of sodium hydroxide, potassium hydroxide, lithiumhydroxide or barium hydroxide, or of a tertiary amine such astriethylamine, or of hydrazine, and in a suitable solvent such asmethanol, ethanol, tetrahydrofuran, N,N-dimethylformamide, water andmixtures thereof. Typically, the reaction is carried out at atemperature ranging from room temperature to about 60° C. and for a timevarying from about 30 minutes to about 96 hours.

According to the conversion described in 1) the reduction of a compoundof formula (VII), wherein R1 is nitro, to a compound of formula (VII)wherein R1 is amino can be carried out in a variety of ways, accordingto conventional methods for reducing a nitro to an amino group.Preferably, this reaction is carried out in a suitable solvent such as,for instance, methanol, ethanol, water, tetrahydrofuran, 1,4-dioxane,N,N-dimethylformamide, acetic acid, or a mixture thereof, in presence ofa suitable reducing agent, such as, for instance, hydrogen and ahydrogenation catalyst, or by treatment with cyclohexene orcyclohexadiene, or formic acid or ammonium formate and a hydrogenationcatalyst, or a metal such as iron or zinc in presence of an inorganicacid, such as hydrochloric acid, or by treatment with tin (II) chloride,at a temperature ranging from 0° C. to reflux and for a time varyingfrom about 1 hour to about 96 hours. The hydrogenation catalyst isusually a metal, most often palladium, which can be used as such orsupported on carbon.

According to the conversion described in 2) the acylation of a compoundof formula (VII), wherein R1 is amino, can be accomplished in a varietyof ways and experimental conditions, which are widely known in the artfor the preparation of carboxamides. As an example, the reaction betweena compound of formula (VII) and a carboxylic acid derivative of formula(VIII), wherein Z is as defined above, can be carried out in presence ofa tertiary base, such as triethylamine, N,N-diisopropylethylamine orpyridine, in a suitable solvent, such as toluene, dichloromethane,chloroform, diethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile,or N,N-dimethylformamide, at a temperature ranging from about −10° C. toreflux and for a period of time varying from about 1 hour to about 96hours.

According to the conversion described in 3) the reaction of a compoundof formula (VII), wherein R1 is amino with an isocyanate of formula(IX), may be carried out in a solvent such as toluene, dichloromethane,chloroform, diethyl ether, tetrahydrofuran, 1,4-dioxane, or acetonitrileat a temperature ranging from about −10° C. to reflux and for a periodof time varying from about 1 hour to about 96 hours.

According to the conversion described in 4) the reaction of a compoundof formula (VII), wherein R1 is amino with a compound of formula (X) maybe accomplished in a variety of ways and experimental conditions whichare widely known in the art for the preparation of sulfonamides. As anexample, the reaction between a compound of formula (VII) and a sulfonylchloride of formula (X), in which case Z is a chlorine atom, can becarried out in a suitable solvent such as, for instance, diethyl ether,tetrahydrofuran, dichloromethane, chloroform, toluene, 1,4-dioxane,acetonitrile and in presence of a proton scavenger such astriethylamine, N,N-diisopropylethylamine, pyridine, at a temperatureranging from about −10° C. to reflux, and for a period of time ranging,for instance, from about 30 min to about 96 hours.

According to the conversion described in 5) the reaction of a compoundof formula (VII), wherein R1 is amino, with an aldehyde or a ketone, canbe conducted in a variety of ways, according to conventional methods forcarrying out reductive alkylation. Preferably, this reaction is carriedout in a suitable solvent such as, for instance, methanol,N,N-dimethylformamide, dichloromethane, tetrahydrofuran, or a mixturethereof, in presence of a suitable reducing agent such as, for instance,sodium borohydride, tetra-alkylammonium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, tetramethylammoniumtriacetoxy borohydride, hydrogen and a hydrogenation catalyst, such asfor instance nickel or platinum or palladium, and in presence of an acidcatalyst, such as, for instance, acetic acid or trifluoroacetic acid, ata temperature ranging from about 0° C. to reflux and for a time varyingfrom about 1 hour to about 96 hours.

A compound of formula (I) can be converted into another compound offormula (I) in a way analogous to that specified above under 5).

The deprotection of a compound of formula (VII) wherein R1 is aprotected amino group, can be made in a variety of ways according toconventional methods for deprotecting amino groups. Depending on theamino protecting group, this reaction can be conducted in differentways. In one aspect, such reaction can be carried out by treatment of acompound of formula (VII) with an inorganic acid, such as hydrochloric,sulphuric or perchloric acid, or an organic acid, such astrifluoroacetic or methanesulfonic acid, in a suitable solvent, such aswater, methanol, ethanol, 1,4-dioxane, tetrahydrofuran, diethyl ether,diisopropyl ether, acetonitrile, N,N-dimethylformamide, dichlorometaneor mixtures thereof, at a temperature ranging from −10° C. to 80° C.,and for a period of time ranging from 30 minutes to 48 hours. In anotheraspect, such reaction can be carried out by treatment of a compound offormula (VII) with an inorganic base, such as lithium or sodium orpotassium hydroxide, or sodium or potassium or caesium carbonate, orwith an organic base, such as triethylamine orN,N-diisopropylethylamine, or with anhydrous hydrazine or hydrazinehydrate in a suitable solvent such as water, methanol, ethanol,1,4-dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether,acetonitrile, N,N-dimethylformamide, dichloromethane or mixturesthereof, at a temperature ranging from −10° C. to 80° C., and for aperiod of time ranging from 30 minutes to 72 hours. In still anotheroption, such reaction can be carried out by treatment of a compound offormula (VII) with hydrogen or cyclohexene or cyclohexadiene and ahydrogenation catalyst, such as palladium on carbon, or with a metal,such as zinc, and an inorganic or organic acid, such as hydrochloric oracetic acid, in a suitable solvent such as water, methanol, ethanol,1,4-dioxane, tetrahydrofuran or mixture thereof, at a temperatureranging from −10° C. to 80° C., and for a period of time ranging from 30minutes to 72 hours.

Substituted pyrrolo[3,4-c]pyrazole derivatives can be prepared usingstandard procedures in organic synthesis as reported, for instance, inSmith, Michael—March's Advanced Organic Chemistry: reactions mechanismsand structure—5^(th) Edition, Michael B. Smith and Jerry March, JohnWiley & Sons Inc., New York (NY), 2001. It is known to the skilledperson that transformation of a chemical function into another mayrequire that one or more reactive centers in the compound containingthis function be protected in order to avoid undesired side reactions.Protection of such reactive centers, and subsequent deprotection at theend of the synthetic transformations, can be accomplished followingstandard procedures described, for instance, in: Green, Theodora W. andWuts, Peter G. M.—Protective Groups in Organic Synthesis, Third Edition,John Wiley & Sons Inc., New York (NY), 1999.

In cases where a compound of formula (I) contains one or more asymmetriccenters, said compound can be separated into the single isomers byprocedures known to those skilled in the art. Such procedures comprisestandard chromatographic techniques, including chromatography using achiral stationary phase, or crystallization. General methods forseparation of compounds containing one or more asymmetric centers arereported, for instance, in Jacques, Jean; Collet, André; Wilen, SamuelH.,—Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., NewYork (NY), 1981.

A compound of formula (I) can also be transformed into apharmaceutically acceptable salt according to standard procedures thatare known to those skilled in the art. Alternatively, a compound offormula (I) that is obtained as a salt can be transformed into the freebase or the free acid according to standard procedures that are known tothe skilled person.

The starting materials of the process of the present invention areeither known or can be prepared according to known methods. As anexample, the preparation of a compound of formula (II), wherein Qrepresents ethyl and Ra and Rb are methyl, is disclosed in theinternational application WO 04/056827 (see, in particular, example 6 atpage 50; this same compound is therein named as5-tert-butyl-1-ethyl-3-amino-6,6-dimethylpyrrolo[3,4-c]pyrazole-2,5(4H,6H)-dicarboxylate).Additional compounds of formula (II), wherein Q represents a lower alkylgroup other than ethyl, can be prepared by applying procedures similarto those disclosed in the above mentioned patent application. Thedesired isomeric form of compounds of formula (II) may be obtained byseparation of the mixture of isomers by methods known in the art.

The compounds of formula (III) and (VIII), for instance those wherein Zrepresents a halogen atom, e.g. a chlorine atom, are either known or canbe easily obtained from the corresponding carboxylic acids, that areeither known or can be prepared by working according to conventionalsynthetic methods. The compounds of formula (VI) and (X), for instancethose wherein Z represents a halogen atom, e.g. a chlorine atom, areeither known or can be prepared from sulfonic acids according toconventional synthetic methods. The compounds of formula (IX) are eitherknown or can be synthesized according to conventional synthetic methodsfor the preparation of isocianates such as, for instance, treatment ofan amine with triphosgene.

Pharmacology

The short forms and abbreviations used herein have the followingmeaning:

Ci Curie DMSO dimethylsulfoxide KDa kiloDalton microCi microCurie mgmilligram microg microgram mL milliliter microL microliter M molar mMmillimolar microM micromolar nM nanomolarAssays

Compounds of the present invention were tested in biochemical as well asin cell-based assays, as described below.

Preparation of IGF-1R for Use in Biochemical Assay

Cloning and Expression

Human cDNA was used as template for amplification by polymerase chainreaction (PCR) of the predicted cytoplasmic portion of IGF-1R (aminoacid residues 960-1367 of precursor protein; see NCBI Entrez ProteinAccession #P08069), which includes the entire kinase domain. PCR wasconducted using the forward primer sequence5′-CTCGGATCCAGAAAGAGAAATAACAGCAGGCTG-3′ (SEQ ID NO: 1) and the reverseprimer sequence 5′-CTCGGATCCTCAGCAGGTCGAAGACTGGGGCAGCGG-3′ (SEQ ID NO:2). In order to facilitate subsequent cloning steps, both primerscomprise a BamHI restriction endonuclease site sequence. This PCRproduct was cloned in frame using BamHI sticky ends into a transfervector for the baculovirus expression system, pVL1392 (Pharmingen),previously modified by insertion into the pVL1392 multiple cloning siteof sequences encoding Glutathione S-transferase (GST) fusion protein,PreScission protease cleavage site and partial MCS cassette derived fromthe pGex-6P plasmid (Amersham BioSciences). Insertion of the IGF-1R PCRproduct described above into the pGex-6P derived BamHI site of themodified pVL1392 vector results in an open reading frame correspondingto the pGEX-6P GST protein and PreScission peptide fused with the humanIGF-1R cytoplasmic domain. In order to obtain fusion protein, Sf21insect cells (Invitrogen) are cotransfected with 2 microg of purifiedplasmid and 1 microg of virus DNA (BaculoGold™ Transfection Kit,Pharmingen), as described in the Baculovirus Instruction manual(Pharmingen). A first amplification of the virus is performed using 600microL of cotransfected virus on 6×10⁶ Sf21 in a monolayer culture, in12 mL of medium (TNM-FH Grace's medium—Pharmingen). After 3 days themedium is collected, centrifuged and transferred to a sterile tube. Asecond amplification is prepared with the same method using 2 mL on3×10⁷ cells, diluted in 40 mL of medium. For the third amplification ofvirus, 1 mL of supernatant from the second round are used per 3×10⁷cells diluted in 40 mL of medium.

Protein expression is performed in H5 insect cells infected with 14 mLvirus/1×10⁹ insect cells (MOI=1.5) for 65 h with shaking at 27° C. Cellsare harvested by centrifugation at 1200×g for 10 minutes.

Protein Purification

Cells were resuspended in phosphate buffered saline solution (PBS), 20mM dithiothreitol (DTT), 0.2% CHAPS, 20% glycerol, 1 mM OVA, “Complete”protease inhibitor cocktail (1 tablet/50 mL buffer; Roche Diagnostics,Milan, Italy) and lysed by liquid extrusion with a Gaulin homogenizer(Niro Soavi, Italy). The lysate was centrifuged at 14000×g for 45minutes and the supernatant was loaded onto a column containing 10 mLGlutathione Sepharose (Amersham Biosciences). The column was firstwashed with PBS buffer for 5 column volumes, then with 100 mM Tris pH8.0, 20% glycerol for 5 column volumes, and lastly eluted with 10 mMglutathione in 100 mM Tris pH 8.0, 20% glycerol. Fractions of 10 mL werecollected, and protein-rich fractions were pooled. Typically, 20 mg offusion protein were recovered from 1×10⁹ cells, and this wastypically >85% pure as judged by SDS-PAGE followed by Coomassiestaining. Purified protein was stored at −80° C. prior to its use inbiochemical assays.

Biochemical Assay for Inhibitors of IGF-1R Kinase Activity

The inhibitory activity of putative kinase inhibitors and the potency ofselected compounds were determined using a trans-phosphorylation assay.

A specific substrate was incubated with the kinase in appropriate bufferconditions in presence of ATP traced with ³³P-γ-ATP (gammaphosphate-labeled, Redivue™ Code Number AH9968, 1000-3000 Ci/mmole,Amersham Biosciences Piscataway, N.J., USA), optimal cofactors and testcompound.

At the end of the phosphorylation reaction, more than 98% cold andradioactive ATP were captured by an excess of Dowex ion exchange resin.The resin was allowed to settle to the bottom of reaction wells bygravity. Supernatant, containing substrate peptide, was subsequentlywithdrawn and transferred into a counting plate, and radioactivity(corresponding to phosphate incorporated into peptide) was evaluated byβ-counting.

Reagents/Assay Conditions

i. Dowex Resin Preparation

500 g of wet resin (SIGMA, custom prepared DOWEX resin 1×8 200-400 mesh,2.5 Kg) were weighed out and diluted to 2 L in 150 mM sodium formate, pH3.00.

The resin was allowed to settle for several hours and then thesupernatant was discarded. This washing procedure was repeated threetimes over two days. Finally, the resin was allowed to settle,supernatant was discarded and two volumes (with respect to the resinvolume) of 150 mM sodium formate buffer were added. The final pH wascirca 3.0. The washed resin was kept at 4° C. before use, and was stablefor more than one week.

ii. Kinase Buffer (KB)

Kinase buffer was composed of 50 mM HEPES pH 7.9 containing 3 mM MnCl₂,1 mM DTT, 3 microM Na₃VO₄, and 0.2 mg/mL BSA. 3×KB is buffer of the samecomposition and pH as KB, but with three times the concentration of eachcomponent.

iii. Enzyme Pre-Activation and Preparation of 3× Enzyme Mix.

Prior to starting the kinase inhibition assay, IGF-1R waspre-phosphorylated in order to linearize reaction kinetics. To achievethis, the desired total quantity of enzyme was prepared at an enzymeconcentration of 360 nM in KB containing 100 microM ATP, and thispreparation was incubated for 30 min at 28° C. 3× Enzyme Mix wasobtained by diluting this preactivated enzyme 20-fold in 3×KB.

iv. Assay Conditions

The kinase assay was run with a final enzyme concentration of 6 nM, inpresence of 6 microM ATP, 1 nM ³³P-γ-ATP and 10 microM substrate, acarboxy-terminally biotinylated peptide of the following sequence:KKKSPGEYVNIEFGGGGGK-biotin (SEQ ID NO: 3). The peptide was obtained inbatches of >95% peptide purity from American Peptide Company, Inc.(Sunnyvale, Calif., USA).

Robotized Dowex Assay

Test reactions were performed in a total final volume of 21 microLconsisting of:

-   a) 7 microL/well of 3× Enzyme Mix (18 nM preactivated enzyme in 3×    kinase buffer),-   b) 7 microL/well of 3× substrate/ATP mix (30 microM substrate, 18    microM ATP, 3 nM ³³P-γ-ATP in double-distilled water (ddH₂O)),-   c) 7 microL/well 3× test compounds diluted into ddH₂O-3% DMSO.    Compound dilution and assay scheme is reported below.    i. Dilution of Compounds

10 mM stock solutions of test compounds in 100% DMSO were distributedinto 96 well 12×8 format microtiter plates.

For % inhibition studies, dilution plates at 1 mM, 100 microM and 10microM were prepared in 100% DMSO, then diluted to 3× final desiredconcentration (30, 3 and 0.3 microM) in ddH₂O, 3% DMSO. A Multimek 96(Beckman Coulter, Inc. 4300 N. Harbor Boulevard, P.O. Box 3100Fullerton, Calif. 92834-3100 USA) was used for compound pipetting intotest plates.

For IC₅₀ determination, starting solutions of 30 microM compound in 3%DMSO were derived from 1 mM/100% DMSO stock solutions. These 30 microMstarting solutions were used for generation of a further 9 serial ⅓dilutions in ddH₂O, 3% DMSO, so as to generate a 10-point dilution curveat 3× the final assay concentration. Serial dilution was conducted in96-well plates using a Biomek 2000 (Beckman Coulter) system. Dilutioncurves of 7 compounds/plate were prepared, and each plate also includeda 10-point dilution curve of Staurosporine, as well as several negativeand positive control wells.

ii. Assay Scheme

7 microL of each test compound dilution (or control) in ddH₂O, 3% DMSOwere pipetted into each well of a 384-well, V-bottom assay plate, whichwas then transferred to a PlateTrak 12 robotized station (Perkin Elmer,45 William Street Wellesley, Mass. 02481-4078, USA) equipped with one384-tip pipetting head for starting the assay, plus one 96-tip head fordispensing the resin) prepared with reservoirs containing sufficient 3×Enzyme mix and 3×ATP mix (3×) to complete the assay run.

At the start of the assay the liquid handling system aspirates 7 microLof ATP mix, introduces an air gap inside the tips (5 microL) and thenaspirates 7 microL of 3× Enzyme Mix. To start the reaction, tipscontents were dispensed into the test wells already containing 7 microLtest compound (at 3× desired final concentration), followed by 3 cyclesof mixing, so as to restore desired final concentration for all reactioncomponents.

Plates were incubated for 60 minutes at room temperature, and then thereaction was stopped by pipetting 70 microL of Dowex resin suspensioninto the reaction mix, followed by three cycles of mixing. Afterstopping the reaction, plates were allowed to rest for one hour in orderto maximize ATP capture. At this point, 20 microL of supernatant weretransferred from each well into wells of 384-Optiplates (Perkin Elmer)containing 70 microL/well of Microscint 40 (Perkin Elmer); after 5 minof orbital shaking the plates were read on a Perkin-Elmer Top Countradioactivity counter.

iii. Data Analysis

Data were analysed using a customized version of the “Assay Explorer”software package (Elsevier MDL, San Leandro, Calif. 94577). For singlecompound concentrations, inhibitory activity was typically expressed as% inhibition obtained in presence of compound, compared to totalactivity of enzyme obtained when inhibitor is omitted. Compounds showingdesired inhibition were further analysed in order to study the potencyof the inhibitor through IC₅₀ calculation. In this case, inhibition dataobtained using serial dilutions of the inhibitor were fitted bynon-linear regression using the following equation:

$v = {v_{0} + \frac{\left( {v_{0} - v_{b}} \right)}{1 + 10^{n({{logIC}_{50} - {\log{\lbrack I\rbrack}}}\;)}}}$where ν_(b) is the baseline velocity, ν is the observed reactionvelocity, ν_(o) is the velocity in the absence of inhibitors, and [I] isthe inhibitor concentration.Cell-Based Assays for Inhibitors of IGF-1R Kinase ActivityWestern Blot Analysis of Receptor Phosphorylation Following Stimulationwith IGF-1 in MCF-7 Human Breast Cancer Cells

MCF-7 cells (ATCC# HTB-22) were seeded in 12-well tissue culture platesat 2×10⁵ cells/well in E-MEM medium (MEM+Earle's BSS+2 mM glutamine+0.1mM non-essential amino acids)+10% FCS, and incubated overnight at 37°C., 5% CO2, 100% relative humidity. Cells were then starved by replacingE-MEM+10% FCS with E-MEM+0.1% BSA, and incubating overnight. After thisincubation, wells were treated with desired concentrations of compoundfor 1 hour at 37° C., and were then stimulated with 10 nM recombinanthuman IGF-1 (Invitrogen, Carlsbad, Calif., USA) for 10 minutes at 37° C.Cells were then washed with PBS and lysed in 100 microL/well cell lysisbuffer (M-PER Mammalian Protein Extraction Reagent [Product #78501,Pierce, Rockford, Ill., USA]+10 mM EDTA+Protease inhibitor cocktail[Sigma-Aldrich product #P8340]+phosphatase inhibitor cocktail[Sigma-Aldrich products #P2850+#P5726]). Cell lysates were cleared bycentrifugation at 10,000×g for 5 minutes, and 10 microg/lane of clearedlysate protein were run on NuPAGE gels (NuPAGE 4-12% 10-lane Bis-Trisgels, Invitrogen) with MOPS running buffer, then transferred ontoHybond-ECL nitrocellulose filters (Amersham Biosciences, LittleChalfont, Buckinghamshire, UK) using Mini PROTEAN II chambers (Bio-RadLaboratories, Hercules, Calif., USA). Filters bearing transferredprotein were incubated for 1 hour in blocking buffer (TBS+5% BSA+0.15%Tween 20), and probed for 2 hours in the same buffer containing 1/1000rabbit anti-phospho IGF-1R Tyr1131/InsR Tyr 1146 antibody (product#3021, Cell Signaling Technology, Beverly, Mass., USA) for the detectionof phosphorylated IGF-1R, or 1/1000 dilution of rabbit IGF-Irβ(H-60)antibody (product #sc-9038, Santa Cruz Biotechnology, Inc., Santa Cruz,Calif., USA) for detecting total IGF-1R β chain. In either case, filterswere then washed for 30 minutes with several changes of TBS+0.15% Tween20, and incubated for 1 hour in washing buffer containing 1/5000dilution of horseradish peroxidase conjugated anti-rabbit IgG (Amersham,product #NA934), then were washed again and developed using the ECLchemiluminescence system (Amersham) according to manufacturer'srecommendations. Unless otherwise stated, reagents used were fromSigma-Aldrich, St. Louis, Mo., USA.

Growth Factor Induced S6 Ribosomal Protein Phosphorylation in PrimaryHuman Fibroblasts.

Phosphorylation of S6 ribosomal protein in response to growth factorstimulation of normal human dermal fibroblasts (NHDF) was used to assesscompound potency in inhibiting IGF-1 induced signal transduction incells, and selectivity towards EGF and PDGF stimulus. NHDF cellsobtained from PromoCell (Heidelberg, Germany), were maintained at 37° C.in a humidified atmosphere with 5% CO₂ in complete Fibroblast GrowthMedium (PromoCell). For assay, NHDF were seeded in 384-well tissueculture plates (clear- and flat-bottomed black plates; MatrixTechnologies Inc., Hudson, N.H., USA) at a density of 5000 cells/well inserum-free medium containing 0.1% bovine serum albumin (BSA) andincubated for 5 days. Starved cells were treated for 1 hour with desireddoses of compounds and then stimulated for a further 2 hours with either10 nM IGF-1 (Invitrogen Corp., CA, USA), 10 nM EGF (Gibco BRL, USA) or 1nM PDGF-B/B (Roche Diagnostics GmbH, Germany). Cells were then fixed inPBS/3.7% paraformaldehyde for 20 minutes at room temperature, washed ×2with PBS, and permeabilized with PBS/0.3% Triton X-100 for 15 minutes.Wells were then saturated with PBS/1% non-fat dry milk (Bio-RadLaboratories, Hercules, Calif., USA) for 1 hour, and then probed for 1hour at 37° C. with anti-phospho-S6 (Ser 235/236) antibody (CellSignaling Technology, Beverly, Mass., USA, cat. #2211) at 1/200 dilutionin PBS/1% milk/0.3% Tween 20. Wells were then washed twice with PBS, andincubated for 1 hour at 37° C. with PBS/1% milk/0.3% Tween 20+1microg/mL DAPI (4,6-diamidino-2-phenylindole)+1/500 Goat anti-rabbitCy5™-conjugated secondary antibody (Amersham Biosciences, LittleChalfont, Buckinghamshire, UK). Wells were then washed ×2 with PBS, and40 microL PBS are left in each well for immunofluorescence analysis.Fluorescence images in the DAPI and Cy5™ channels were automaticallyacquired, stored and analysed using a Cellomics ArrayScan™ IV instrument(Cellomics, Pittsburgh, USA); the Cellomics Cytotoxicity Algorithm wasused to quantify cytoplasmic fluorescence associated with phospho-S6(Cy5™ signal parameter: “Mean Lyso Mass-pH”) for each cell in 10fields/well, and eventually expressed as a mean population value. Unlessotherwise stated, reagents were obtained from Sigma-Aldrich, St. Louis,Mo., USA.

Biochemical Assay for Inhibitors of Aurora-2 Kinase Activity

The in vitro kinase inhibition assay was conducted in the same way asdescribed for IGF-1R. At variance with IGF-1R, Aurora-2 enzyme does notneed pre-activation.

i. Kinase Buffer (KB) for Aurora-2

The kinase buffer was composed of 50 mM HEPES, pH 7.0, 10 mM MnCl₂, 1 mMDTT, 3 microM Na₃VO₄, and 0.2 mg/mL BSA.

ii. Assay Conditions for Aurora-2 (Final Concentrations)

The kinase assay was run with an enzyme concentration of 2.5 nM, 10microM ATP, 1 nM ³³P-γ-ATP, and 8 microM substrate, composed of 4LRRWSLG (SEQ ID NO: 4) repeats.

In Vitro Cell Proliferation Assay for Inhibitors of Aurora-2 KinaseActivity

The human colon cancer cell line HCT-116 was seeded at 5000 cells/cm² in24 wells plate (Costar) using F12 medium (Gibco) supplemented with 10%FCS (EuroClone, Italy) 2 mM L-glutamine and 1% penicillin/streptomycinand maintained at 37° C., 5% CO₂ and 96% relative humidity. Thefollowing day, plates were treated in duplicates with 5 mL of anappropriate dilution of compounds starting from a 10 mM stock in DMSO.Two untreated control wells were included in each plate. After 72 hoursof treatment, medium was withdrawn and cells detached from each wellusing 0.5 mL of 0.05% (w/v) Trypsin, 0.02% (w/v) EDTA (Gibco). Sampleswere diluted with 9.5 mL of Isoton (Coulter) and counted using aMultisizer 3 cell counter (Beckman Coulter). Data were evaluated aspercent of the control wells:% of CTR=(Treated−Blank)/(Control−Blank).IC₅₀ values were calculated by LSW/Data Analysis using Microsoft Excelsigmoidal curve fitting.

Biochemical and cell-based assay data for representative compounds arereported in Table 1.

TABLE 1 Inhibition of IGF1-induced IGF1R IC₅₀ (μM) S6 phosphorylationCompound Biochemical assay IC₅₀ (μM) 1 0.17 0.74 11 0.09 0.30 90 0.465.3

The same compounds were tested for inhibition of IGF1-induced IGF1Rphosphorylation in MCF-7 cells and results are shown in FIG. 1.

The compounds of the present invention can be administered either assingle agents or, alternatively, in combination with known anticancertreatments such as radiation therapy or chemotherapy regimen incombination with, for example, antihormonal agents such asantiestrogens, antiandrogens and aromatase inhibitors, topoisomerase Iinhibitors, topoisomerase II inhibitors, agents that targetmicrotubules, platin-based agents, alkylating agents, DNA damaging orintercalating agents, antineoplastic antimetabolites, other kinaseinhibitors, other anti-angiogenic agents, inhibitors of kinesins,therapeutic monoclonal antibodies, inhibitors of mTOR, histonedeacetylase inhibitors, farnesyl transferase inhibitors, and inhibitorsof hypoxic response.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent within the approved dosagerange.

Compounds of formula (I) may be used sequentially with known anticanceragents when a combination formulation is inappropriate.

The compounds of formula (I) of the present invention, suitable foradministration to a mammal, e.g., to humans, can be administered by theusual routes and the dosage level depends upon the age, weight, andconditions of the patient and administration route. For example, asuitable dosage adopted for oral administration of a compound of formula(I) may range from about 10 to about 500 mg per dose, from 1 to 5 timesdaily. The compounds of the invention can be administered in a varietyof dosage forms, e.g., orally, in the form tablets, capsules, sugar orfilm coated tablets, liquid solutions or suspensions; rectally in theform suppositories; parenterally, e.g., intramuscularly, or throughintravenous and/or intrathecal and/or intraspinal injection or infusion.

The present invention also includes pharmaceutical compositionscomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof in association with a pharmaceutically acceptableexcipient, which may be a carrier or a diluent.

The pharmaceutical compositions containing the compounds of theinvention are usually prepared following conventional methods and areadministered in a suitable pharmaceutical form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g., lactose, dextrose saccharose, sucrose,cellulose, corn starch or potato starch; lubricants, e.g., silica, talc,stearic acid, magnesium or calcium stearate, and/or polyethyleneglycols; binding agents, e.g., starches, arabic gum, gelatinemethylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone;disintegrating agents, e.g., starch, alginic acid, alginates or sodiumstarch glycolate; effervescing mixtures; dyestuffs; sweeteners; wettingagents such as lecithin, polysorbates, laurylsulphates; and, in general,non-toxic and pharmacologically inactive substances used inpharmaceutical formulations. These pharmaceutical preparations may bemanufactured in known manner, for example, by means of mixing,granulating, tabletting, sugar-coating, or film-coating processes.

The liquid dispersions for oral administration may be, e.g., syrups,emulsions and suspensions.

As an example the syrups may contain, as a carrier, saccharose orsaccharose with glycerine and/or mannitol and sorbitol.

The suspensions and the emulsions may contain, as examples of carriers,natural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose or polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain,together with the active compound, a pharmaceutically acceptablecarrier, e.g., sterile water, olive oil, ethyl oleate, glycols, e.g.,propylene glycol and, if desired, a suitable amount of lidocainehydrochloride.

The solutions for intravenous injections or infusions may contain, as acarrier, sterile water or preferably they may be in the form of sterile,aqueous, isotonic, saline solutions or they may contain propylene glycolas a carrier.

The suppositories may contain, together with the active compound, apharmaceutically acceptable carrier, e.g., cocoa butter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

With the aim to better illustrate the present invention, without posingany limitation to it, the following examples are now given.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the inhibition of IGF1R auto-phosphorylation in MCF-7starved cells stimulated with 10 nM IGF1 by compounds of formula (I),exemplified by compound 1, 11, and 90.

Treatment of starved MCF-7 cells with 10 nM IGF1 induced receptorauto-phosphorylation as shown by the appearance of a more intense bandof phosphorylated IGF1R (pIGF1R). Incubation of cells with increasingconcentrations of compound 1, 11, and 90 prior to treatment with IGF1resulted in inhibition of IGF1-induced IGF1R auto-phosphorylation asshown by the disappearance of the band of phosphorylated IGF1R (pIGF1R).

EXPERIMENTAL SECTION

General Purification and Analytical Methods

Flash Chromatography was performed on silica gel (Merck grade 9395,60A). HPLC was performed on Waters X Terra RP 18 (4.6×50 mm, 3.5 μm)column using a Waters 2790 HPLC system equipped with a 996 Waters PDAdetector and Micromass mod. ZQ single quadrupole mass spectrometer,equipped with an electrospray (ESI) ion source. Mobile phase A wasammonium acetate 5 mM buffer (pH 5.5 with acetic acid-acetonitrile95:5), and Mobile phase B was water-acetonitrile (5:95). Gradient from10 to 90% B in 8 minutes, hold 90% B 2 minutes. UV detection at 220 nmand 254 nm. Flow rate 1 mL/min. Injection volume 10 microL. Full scan,mass range from 100 to 800 amu. Capillary voltage was 2.5 KV; sourcetemperature was 120° C.; cone was 10 V. Retention times (HPLC r.t.) aregiven in minutes at 220 nm or at 254 nm Mass are given as m/z ratio.

When necessary, compounds were purified by preparative HPLC on a WatersSymmetry C18 (19×50 mm, 5 um) column or on a Waters X Terra RP 18(30×150 mm, 5 μm) column using a Waters preparative HPLC 600 equippedwith a 996 Waters PDA detector and a Micromass mod. ZMD singlequadrupole mass spectrometer, electron spray ionization, positive mode.Mobile phase A was water-0.01% trifluoroacetic acid, and mobile phase Bwas acetonitrile. Gradient from 10 to 90% B in 8 min, hold 90% B 2 min.Flow rate 20 mL/min. In alternative, mobile phase A was water-0.1% NH₃,and mobile phase B was acetonitrile. Gradient from 10 to 100% B in 8min, hold 100% B 2 min. Flow rate 20 mL/min.

1H-NMR spectrometry was performed on a Mercury VX 400 operating at400.45 MHz equipped with a 5 mm double resonance probe [1H (15N-31P)ID_PFG Varian].

Example 1 Preparation of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoicacid Step 1 Preparation of 4-fluoro-2-nitro-benzoic acid tert-butylester

A solution of 4-fluoro-2-nitro-benzoic acid (10 g, 54 mmol),di-tert-butyl-dicarbonate (2 eq., 23.6 g, 108 mmol) and4-dimethylaminopyridine (0.3 eq., 1.98 g, 16.2 mmol) in tert-butanol(100 mL) and dichloromethane (100 mL) was stiffed at room temperaturefor about 20 hours. The reaction mixture was then diluted with ethylacetate (500 mL), washed with 1N HCl (500 mL), water (500 mL), brine(500 mL), dried over sodium sulfate and evaporated to dryness. The titlecompound was obtained as pale yellow oil (quantitative) and it was usedin the next step without further purification.

1H-NMR (400 MHz),

(ppm, DMSO-d₆): 8.04 (dd, J=8.47, 2.50 Hz, 1H) 7.95 (dd, J=8.66, 5.37Hz, 1H) 7.71 (ddd, J=8.66, 8.17, 2.56 Hz, 1H) 1.51 (s, 9H).

Step 2 Preparation of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acidtert-butyl ester

A solution of 4-fluoro-2-nitro-benzoic acid tert-butyl ester (13 g, 54mmol) and N-methyl-piperazine (17 mL) was stirred at room temperaturefor about 6 hours. The reaction mixture was then diluted with water (800mL) and maintained under magnetic stirring for about 20 hours. Theresulting solid was filtered, washed thoroughly with water and driedunder vacuum at 40° C. The title compound was obtained as a yellow solid(16.4 g, 94% yield), and was used in the next step without any furtherpurification.

1H-NMR (400 MHz).

(ppm, DMSO-d₆): 7.69 (d, J=8.90 Hz, 1H) 7.29 (d, J=2.56 Hz, 1H), 7.15(dd, J1=8.90 Hz, J2=2.56 Hz, 1H), 3.37 (m, 4H), 2.44 (m, 4H), 1.46 (s,9H).

Operating in an analogous way, and using the suitable amine, thefollowing compounds were obtained:

4-morpholin-4-yl-2-nitro-benzoic acid tert-butyl ester

1H-NMR (400 MHz),

(ppm, DMSO-d₆): 7.71 (d, J=8.77 Hz, 1H), 7.31 (d, J=2.44 Hz, 1H), 7.17(dd, J1=8.77 Hz, J2=2.44 Hz, 1H), 3.73 (m, 4H), 3.35 (m, 4H), 1.46 (s,9H).

4-dimethylamino-2-nitro-benzoic acid tert-butyl ester

1H-NMR (400 MHz),

(ppm, DMSO-d₆): 7.69 (d, J=8.90 Hz, 1H), 6.99 (d, J=2.68 Hz, 1H), 6.89(dd, J1=8.90 Hz, J2=2.68 Hz, 1H), 3.04 (s, 6H), 1.46 (s, 9H).

Step 3 Preparation of 4-(4-methyl-piperazin-1-yl)-2-nitro-benzoic acidhydrochloride

A mixture of tert-butyl 4-(4-methyl-piperazin-1-yl)-2-nitro benzoate(16.4 g, 51 mmol) and 37% HCl (100 mL) in 1,4-dioxane (200 mL) wasstirred at room temperature for about 4 hours. The resulting solid wasfiltered, washed thoroughly with 1,4-dioxane and dried under vacuum at45° C. The title compound was obtained as pale yellow solid (13.45 g,87.5% yield) and it was used in the next step without furtherpurification.

1H-NMR (400 MHz),

(ppm. DMSO-d₆): 10.27 (bs, 1H), 7.81 (d, J=8.90 Hz, 1H), 7.40 (d, J=2.69Hz, 1H), 7.24 (dd, J1=8.90 Hz, J2=2.69 Hz, 1H), 4.13 (bs, 2H), 3.55-3.06(bs, 6H), 2.83 (s, 3H).

Operating in an analogous way, the following compounds were obtained:

4-morpholin-4-yl-2-nitro-benzoic acid

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.98 (bs, 1H), 7.78 (d, J=8.91 Hz,1H), 7.30 (d, J=2.44 Hz, 1H), 7.15 (dd, J1=8.91 Hz, J2=2.44 Hz, 1H),3.73 (m, 4H), 3.33 (m, 4H).

4-dimethylamino-2-nitro-benzoic acid

1H-NMR (400 MHz),

(ppm. DMSO-d₆): 12.81 (bs, 1H), 7.72 (d, J=8.90 Hz, 1H), 6.96 (d, J=2.57Hz, 1H), 6.84 (dd, J1=8.90 Hz, J2=2.58 Hz, 1H), 3.01 (s, 6H).

Example 2 Preparation of 3-pyrrolidin-1-ylmethyl-benzoyl chloridehydrochloride Step 1 Preparation of 3-pyrrolidin-1-ylmethyl-benzoic acidmethyl ester

To a stirred solution of pyrrolidine (7.3 mL, 87 mmol) in drytetrahydrofuran (5 mL), a solution of 3-bromomethyl-benzoic acid methylester (2.0 g, 8.7 mmol) in 5 mL of dry tetrahydrofuran was addeddropwise and the mixture stirred at room temperature for 4 hours. Thereaction mixture was then poured into 100 mL of saturated aqueoussolution of sodium hydrogenocarbonate, extracted with 100 mL of ethylacetate, dried over sodium sulfate and evaporated to dryness affordingthe title compound as yellow oil (1.85 g).

1H-NMR (400 MHz),

(ppm, DMSO-d₆): 7.91 (m, 1H), 7.85 (m, 1H), 7.59 (m, 1H), 7.48 (m, 1H),3.86 (s, 3H), 3.64 (s, 2H), 2.44 (m, 4H), 1.71 (m, 4H).

Step 2

Preparation of 3-pyrrolidin-1-ylmethyl-benzoic acid hydrochloride

A solution of 3-pyrrolidin-1-ylmethyl-benzoic acid methyl ester (800 mg,3.6 mmol) in aqueous 25% hydrochloric acid (15 mL) was stirred at 90° C.for 4 hours. The solvent was evaporated affording the title compound asbrown oil (quantitative) that was used as such for the next step.

Step 3

Preparation of 3-pyrrolidin-1-ylmethyl-benzoyl chloride hydrochloride

A suspension of 3-pyrrolidin-1-ylmethyl-benzoic acid hydrochloride (850mg, 3.5 mmol) in dry tetrahydrofuran was treated with 2.55 mL of thionylchloride (35 mmol, 10 eq) and stirred at room temperature for 2 hours.The solution thus obtained was then evaporated to dryness, the residuesuspended in dry toluene, evaporated to dryness and dried under vacuumaffording the title compound as pale brown solid (quantitative).

Example 3 Preparation of6,6-Dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylicacid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra═Rb=methyl,A=D=E=CH, B=CR2, R1=nitro, R2=4-methyl-piperazin-1-yl]

4-(4-methylpiperazin-1-yl)-2-nitrobenzoic acid (15 g, 49.7 mmol) in drytetrahydrofuran (100 mL) was treated with thionyl chloride (5 eq., 18.1mL, 248.7 mmol) and few drops of N,N-dimethylformamide at 80° C. for 14hours. After removal of the solvent under vacuum, the crude material wasadded portion-wise to a solution of3-amino-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid5-tert-butyl ester 2-ethyl ester (16.1 g, 49.7 mmol) anddiisopropylethylamine (5 eq., 43.4 mL, 248.7 mmol) in 1,4-dioxane (200mL) maintained under magnetic stirring at 80° C. The reaction mixturewas stirred for about 6 hours at 80° C. After removal of the solvent,the crude material was diluted with dichloromethane (200 mL), saturatedsodium hydrogenocarbonate (200 mL), dried over sodium sulfate,evaporated to dryness and purified by flash chromatography on silicagel, using acetone as eluant. The title compound was obtained as lightyellow powder (13.5 g, 47% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.70, 10.67 (s, 1H), 7.68, 7.66 (d,J1=8.78 Hz, 1H), 7.48 (bs, 1H), 7.30 (dd, J1=8.78 Hz, J2=2.56 Hz, 1H),4.47-4.39 (m, 4H), 3.41 (m, 4H), 2.52 (m, 4H), 2.27 (s, 3H), 1.63, 1.62(s, 6H), 1.49, 1.46 (s, 9H), 1.37, 1.36 (t, J=7.07 Hz, 3H), mixture ofrotamers.

Operating in an analogous way, and using the suitable carboxylic acid,the following compounds were also obtained:

6,6-dimethyl-3-(2-nitro-benzoylamino)-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylicacid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra═Rb=methyl,A=B=D=E=CH, R1=nitro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.97, 10.94 (s, 1H), 8.27, 8.21 (d,J=8.05 Hz, 1H), 7.98-7.76 (m, 3H), 4.55-4.48, 4.46-4.38 (m, 4H), 1.65,1.63 (s, 6H), 1.50, 1.46 (s, 9H), 1.35, 1.34 (t, 3H), mixture ofrotamers.

6,6-Dimethyl-3-(4-morpholin-4-yl-2-nitro-benzoylamino)-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylicacid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra═Rb=methyl,A=D=E=CH, B=CR2, R1=nitro, R2=4-morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.68 (s, 1H), 7.68, 7.66 (d, J=8.65Hz, 1H), 7.47 (d, 1H), 7.29 (dd, J=8.65 Hz, J2=2.56 Hz, 1H), 4.45-4.36(m, 4H), 3.73 (m, 4H), 3.34 (m, 4H), 1.61, 1.59 (s, 6H), 1.47, 1.43 (s,9H), 1.34, 1.33 (t, J=7.08 Hz, 3H), mixture of rotamers.

3-(4-Dimethylamino-2-nitro-benzoylamino)-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylicacid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra═Rb=methyl,A=D=E=CH, B=CR2, R1=nitro, R2=4-dimethylamino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.65, 10.62 (bs, 1H), 7.67, 7.66(d, J1=8.70 Hz, 1H), 7.18 (bs, 1H), 7.01 (dd, J1=8.70 Hz, J2=2.56 Hz,1H), 4.47-4.41 (m, 4H), 3.07 (s, 6H), 1.63, 1.61 (s, 6H), 1.49, 1.46 (s,9H), 1.37, 1.36 (t, J=7.07 Hz, 3H), mixture of rotamers.

3-(4-Methoxy-2-nitro-benzoylamino)-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylicacid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra═Rb=methyl,A=D=E=CH, B=CR2, R1=nitro, R2=methoxy]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.84, 10.81 (2 bs, 1H), 7.80-7.74(m, 1H), 7.71-7.66 (m, 1H), 7.47-7.43 (m, 1H), 4.46-4.33 (m, 4H), 3.94(s, 3H), 1.64, 1.63 (2bs, 6H), 1.51-1.44 (m, 9H), 1.38-1.32 (m, 3H).

3-(4-Fluoro-2-nitro-benzoylamino)-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylicacid 5-tert-butyl ester 2-ethyl ester [(IV) Q=ethyl, Ra═Rb=methyl,A=D=E=CH, B=CR2, R1=nitro, R2=fluoro]

ESI (+) MS: m/z 492 (MH⁺).

3-(2-Fluoro-6-nitro-benzoylamino)-6,6-dimethyl-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylicacid 5-tert-butyl ester 1-ethyl ester [(IV) Q=ethyl, Ra═Rb=methyl,A=B=D=CH, E=CR2, R1=nitro, R2=fluoro]

1H-NMR (400 MHz), 6 ppm, CDCl₃): 11.37 (bs, 1H), 8.15 (s, 1H), 8.0 (t,1H), 7.65 (t, 1H), 7.53 (t, 1H), 4.69 (m, 2H), 4.50 (q, 2H), 1.85 (s,6H), 1.50 (s, 9H), 1.47 (t, 3H).

Example 4 Preparation of6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester dihydrochloride [(V) Q=ethyl, Ra═Rb=methyl, A=D=E=CH,B=CR2, R1=nitro, R2=4-methyl-piperazin-1-yl]

A solution of 4N HCl in 1,4-dioxane (4 eq., 18.4 mL, 73.6 mmol) wasadded to a solution of6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylicacid 5-tert-butyl ester 2-ethyl ester (10.5 g, 18.4 mmol) in 1,4-dioxane(100 mL) at room temperature. Stirring was continued for about 30 hours.After removal of the solvent, the crude material was treated withdiethyl ether (2×100 mL) and evaporated to dryness. The title compoundwas obtained after crystallization from diethyl ether as yellow solid(10 g, quantitative).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.88 (s, 2H), 9.94 (bs, 1H), 7.75(d, J1=8.78 Hz, 1H), 7.61 (d, J2=2.56 Hz, 1H), 7.40 (dd, J1=8.78 Hz,J2=2.56 Hz, 1H), 4.50-4.43 (m, 4H), 4.14 (m, 2H), 3.51 (m, 2H),3.45-3.05 (m, 4H), 2.84 (s, 3H), 1.69 (s, 6H), 1.37 (t, J=7.07 Hz, 3H).

Operating in an analogous way, the following compounds were obtained:

6,6-Dimethyl-3-(2-nitro-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester hydrochloride [(V) Q=ethyl, Ra═Rb=methyl, A=B=D=E=CH,R1=nitro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.16 (s, 1H), 10.02, 9.84 (bs, 1H),8.28, 8.22 (dd, J1=8.17 Hz, J2=0.85 Hz, 1H), 7.95 (ddd, J1=8.05 Hz,J2=7.43 Hz, J3=0.85 Hz, 1H), 7.85 (ddd, J1=8.17 Hz, J2=8.05 Hz, J3=1.47Hz, 1H), 7.79 (dd, J1=7.43 Hz, J2=1.47 Hz, 1H), 4.58, 4.44 (q, J=7.08Hz, 2H), 4.51, 4.31 (s, 2H), 1.70 (s, 6H), 1.41, 1.35 (t, J=7.08 Hz,3H), mixture of rotamers.

6,6-Dimethyl-3-(4-morpholin-4-yl-2-nitro-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester hydrochloride [(V) Q=ethyl, Ra═Rb=methyl,A=D=E=CH, B=CR2, R1=nitro, R2=morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.56 (s, 1H), 7.68 (d, J1=8.66 Hz,1H), 7.46 (d, J2=2.44 Hz, 1H), 7.29 (dd, J1=8.66 Hz, J2=2.44 Hz, 1H),4.40 (q, J=7.07 Hz, 2H), 3.88 (s, 2H), 3.75 (m, 4H), 3.34 (m, 4H),1.37-1.32 (m, 9H).

3-(4-Dimethylamino-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester hydrochloride [(V) Q=ethyl, Ra═Rb=methyl, A=D=E=CH,B=CR2, R1=nitro, R2=dimethylamino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.78 (s, 1H), 9.83 (bs, NH2+), 7.67(d, J1=8.90 Hz, 1H), 7.18 (d, J2=2.56 Hz, 1H), 7.02 (dd, J1=8.90 Hz,J2=2.56 Hz, 1H), 4.50 (m, 2H), 4.47 (q, J=7.08 Hz, 2H), 3.08 (s, 6H),1.68 (s, 6H), 1.38 (t, J=7.08 Hz, 3H).

3-(4-Methoxy-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(V) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2, R1=nitro,R2=methoxy]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.01 (s, 1H), 9.91 (bs, 2H), 7.79(d, J=8.5 Hz, 1H), 7.69 (d, J=2.6 Hz, 1H), 7.47 (dd, J1=2.6 Hz, J2=8.5Hz, 1H), 4.49 (m, 2H), 4.45 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 1.69 (s,6H), 1.37 (t, J=7.2 Hz, 3H).

3-(4-Fluoro-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester hydrochloride [(V) Q=ethyl, Ra═Rb=methyl, A=D=E=CH,B=CR2, R1=nitro, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.17 (s, 1H), 9.88 (bs, NH2+), 8.19(dd, J1=8.77 Hz, J2=2.08 Hz, 1H), 7.91-7.83 (m, 2H), 4.50 (bs, 2H), 4.43(q, J=7.08 Hz, 2H), 1.70 (s, 6H), 1.35 (t, J=7.08 Hz, 3H).

3-(2-Fluoro-6-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylicacid ethyl ester hydrochloride [(V) Q=ethyl, Ra═Rb=methyl, A=B=D=CH,E=CR2, R1=nitro, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 9.9 (bs, 1H), 8.75 (bs, 2H), 8.09(d, 1H), 7.85 (m, 2H), 4.21 (q, 2H), 3.05 (m, 2H), 1.85 (s, 6H), 1.42(t, 3H).

Example 5 Preparation of5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=nitro, R2=4-methyl-piperazin-1-yl]

3,5-Difluorobenzesulfonyl chloride (1 eq., 3.9 g, 18.4 mmol) was addedportion-wise to a stirred solution of6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester dihydrochloride (10 g, 18.4 mmol) andN,N-diisopropylethylamine (6 eq., 19.3 mL, 110.4 mmol) in drydichloromethane (100 mL) at room temperature. Stirring was continued for4 hours. The reaction mixture was diluted with dichloromethane (100 mL)then washed with saturated sodium hydrogenocarbonate (150 mL), driedover sodium sulfate, evaporated to dryness and purified by flashchromatography on silica gel, using acetone as eluant. The titlecompound was obtained as yellow solid (9 g, 65% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.71 (s, 1H), 7.69-7.62 (m, 4H),7.47 (d, J2=2.44 Hz, 1H), 7.29 (dd, J1=9.03 Hz, J2=2.44 Hz, 1H), 4.58(s, 2H), 4.43 (q, J=7.07 Hz, 2H), 3.41 (m, 4H), 2.50 (m, 4H), 2.26 (s,3H), 1.67 (s, 6H), 1.35 (t, J=7.07 Hz, 3H).

Operating in an analogous way, the following compounds were obtained:

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-(2-nitro-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=B=D=E=CH,R=3,5-difluorophenyl, R1=nitro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.02 (s, 1H), 8.22 (dd, J1=8.17 Hz,J2=0.86 Hz, 1H), 7.93 (ddd, J1=8.05 Hz, J2=7.44 Hz, J3=0.86 Hz, 1H),7.83 (ddd, J1=8.17 Hz, J2=8.05 Hz, J3=1.46 Hz, 1H), 7.78 (dd, J1=7.44Hz, J2=1.46 Hz, 1H), 7.68 (m, 1H), 7.64 (m, 2H), 4.62, 4.59 (s, 2H),4.51, 4.41 (q, J=7.07 Hz, 2H), 1.70 (s, 6H), 1.37, 1.33 (t, J=7.07 Hz,3H), mixture of rotamers.

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-(4-morpholin-4-yl-2-nitro-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=nitro, R2=morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.71 (s, 1H), 7.66 (d, J1=8.78 Hz,1H), 7.67-7.59 (m, 3H), 7.46 (d, J2=2.56 Hz, 1H), 7.28 (dd, J1=8.78 Hz,J2=2.56 Hz, 1H), 4.56 (s, 2H), 4.40 (q, J=7.07 Hz, 2H), 3.73 (m, 4H),3.35 (m, 4H), 1.65 (s, 6H), 1.32 (t, J=7.07 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-(4-dimethylamino-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=nitro, R2=dimethylamino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.64 (s, 1H), 7.66-7.59 (m, 4H),7.16 (d, J2=2.56 Hz, 1H), 6.98 (dd, J1=8.90 Hz, J2=2.56 Hz, 1H), 4.56(s, 2H), 4.41 (q, J=7.08 Hz, 2H), 3.04 (s, 6H), 1.64 (s, 6H), 1.33 (t,J=7.08 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-(4-methoxy-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=nitro, R2=methoxy]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.88 (s, 1H), 7.77 (d, J=8.5 Hz,1H), 7.70-7.62 (m, 4H), 7.46 (dd, J1=2.6 Hz, J2=8.5 Hz, 1H), 4.58 (bs,2H), 4.42 (q, J=7.1 Hz, 2H), 3.94 (s, 3H), 1.69 (s, 6H), 1.34 (t, J=7.1Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-(4-fluoro-2-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=nitro, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.03 (s, 1H), 8.16 (dd, J1=8.65 Hz,J2=2.44 Hz, 1H), 7.90-7.82 (m, 2H), 7.71-7.62 (m, 3H), 4.58 (s, 2H),4.41 (q, J=7.07 Hz, 2H), 1.69 (s, 6H), 1.33 (t, J=7.07 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-(2-fluoro-6-nitro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=B=D=CH, E=CR2,R=3,5-difluorophenyl, R1=nitro, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.03 (s, 1H), 8.11 (d, 1H),7.80-7.89 (m, 2H), 7.66-7.72 (m, 3H), 4.61 (s, 2H), 4.42 (q, 3H), 1.86(s, 6H), 1.34 (t, 3H).

Example 6 Preparation of3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester hydrochloride [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH,B=CR2, R=3,5-difluorophenyl, R1=amino, R2=4-methyl-piperazin-1-yl]

A suspension of5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-[4-(4-methyl-piperazin-1-yl)-2-nitro-benzoylamino]-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (1.50 g, 2.3 mmol), cyclohexene (15 eq., 20 mL), 2N HCl(13 eq., 15 mL), in THF/water/ethanol (2:1.5:1.5, 50 mL) was treatedwith 10% Pd—C (0.2 eq., 0.55 g). The reaction mixture was stirred at 70°C. for 3 hours, then filtered, washed thoroughly with THF, followed byethanol and evaporated to dryness. The title compound was obtained asbeige powder (1.4 g, 93% yield) and it was used in the next stepswithout further purification.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.60, 10.40 (bs, 1H), 7.64 (m, 3H),7.34 (d, J1=9.02 Hz, 1H), 6.68 (bs, NH3+), 6.39 (dd, J1=9.02 Hz, J2=2.31Hz, 1H), 6.26 (d, J2=2.31 Hz, 1H), 4.71 (s, 2H), 4.43 (q, J=7.07 Hz,2H), 3.88 (m, 2H), 3.48 (m, 2H), 3.11 (m, 4H), 2.81, 2.80 (s, 3H), 1.63(s, 6H), 1.34 (t, J=7.07 Hz, 3H), mixture of rotamers.

Example 7 Preparation of3-(2-amino-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=B=D=E=CH,R=3,5-difluorophenyl, R1=amino]

A suspension of5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-(2-nitro-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (8.0 g, 0.017 mol) cyclohexene (20 mL) in dioxane (200mL) was heated at 90° C. and 5% Pd/C (1.0 g) was carefully added insmall portions. Stiffing was continued for 5 hours at 90° C., then thecatalyst was filtered through Celite and the pad washed with warm1,4-dioxane (100 mL). After evaporation of the solvent, the crudematerial was suspended in hexane (100 mL), stirred for about 30 minutesand filtered to yield the title compound as beige solid (7.2 g, 95%yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.66 (m, 3H), 7.48 (dd, J1=8.05 Hz,J2=1.34 Hz, 1H), 7.29 (ddd, J1=8.54 Hz, J2=6.95 Hz, J3=1.34 Hz, 1H),6.83 (dd, J1=8.54 Hz, J2=0.85 Hz, 1H), 6.65 (ddd, J1=8.05 Hz, J2=6.95Hz, J3=0.85 Hz, 1H), 4.75 (s, 2H), 4.46 (q, J=7.08 Hz, 2H), 1.66 (s,6H), 1.36 (t, J=7.08 Hz, 3H).

Operating in an analogous way, the following compounds were obtained:

3-(2-Amino-4-morpholin-4-yl-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=amino, R2=morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.54 (bs, 1H), 7.65-7.60 (m, 3H),7.30 (d, J1=9.03 Hz, 1H), 6.34 (dd, J1=9.03 Hz, J2=2.44 Hz, 1H), 6.20(d, J2=2.44 Hz, 1H), 4.71 (s, 2H), 4.43 (q, J=7.08 Hz, 2H), 3.70 (m,4H), 3.17 (m, 4H), 1.63 (s, 6H), 1.34 (t, J=7.08 Hz, 3H).

3-(2-Amino-4-dimethylamino-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=amino, R2=dimethylamino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.66 (bs, 1H), 7.65 (m, 2H), 7.29(d, J1=9.03 Hz, 1H), 7.18 (m, 1H), 6.18 (dd, J1=9.03 Hz, J2=2.57 Hz,1H), 6.01 (d, J2=2.57 Hz, 1H), 4.73 (s, 2H), 4.46 (q, J=7.08 Hz, 2H),2.96 (s, 6H), 1.65 (s, 6H), 1.37 (t, J=7.08 Hz, 3H).

3-(2-Amino-4-methoxy-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=amino, R2=methoxy]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.57 (bs, 1H), 7.70-7.62 (m, 3H),7.41 (d, J=8.9 Hz, 1H), 6.84 (bs, 2H), 6.35 (d, J=2.5 Hz, 1H), 6.28 (dd,J1=2.5 Hz, J2=8.9 Hz, 1H), 4.74 (bs, 2H), 4.46 (q, J=7.1 Hz, 2H), 3.76(s, 3H), 1.66 (s, 6H), 1.36 (t, J=7.1 Hz, 3H).

3-(2-Amino-4-fluoro-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=amino, R2=fluoro]

ESI (+) MS: m/z 538 (MH⁺).

3-(2-Amino-6-fluoro-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=B=D=CH, E=CR2,R=3,5-difluorophenyl, R1=amino, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.24 (s, 1H), 7.65 (m, 3H), 7.12(m, 1H), 6.58 (d, 1H), 6.34 (m, 1H), 5.92 (s, 2H), 4.70 (s, 2H), 4.42(q, 2H), 1.83 (s, 6H), 1.34 (t, 3H).

Example 8 Preparation of 1-methyl-1H-pyrrole-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(1-methyl-1H-pyrrole-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl],cpd. 12

1-Methyl-1H-pyrrole-2-carbonyl chloride (3 eq., 0.225 g, 1.57 mmol) wasadded to the mixture of3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester hydrochloride (0.34 g, 0.52 mmol) andN,N-diisopropylethylamine (6 eq., 0.54 mL, 3.12 mmol) in drydichloromethane (10 mL), maintained under stirring at room temperature.After 2 hours, 1-methyl-1H-pyrrole-2-carbonyl chloride (5 eq., 0.4 g)and N,N-diisopropylethylamine (22 eq., 2 mL) were added and stirring wascontinued for 20 hours. The mixture was diluted with dichloromethane(100 mL), washed with saturated sodium hydrogenocarbonate (100 mL),dried over sodium sulfate and evaporated to dryness. The crude materialwas then treated with triethylamine (5 mL) and methanol (20 mL) at roomtemperature for 20 hours. After removal of the solvent, the mixture waspurified by flash chromatography on silica gel, usingdichloromethane-methanol-30% NH₄OH 100:10:1 as eluant, to yield thetitle compound (0.145 g, 42% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.56, 12.46 (bs, 1H), 12.26 (bs,1H), 10.87, 10.83 (bs, 1H), 8.30 (bs, 1H), 7.95, 7.82 (m, bs, 1H), 7.68(m, 1H), 7.59 (m, 2H), 7.09 (m, 1H), 6.88, 6.84 (m, bs, 1H), 6.76, 6.68(m, bs, 1H), 6.15 (m, 1H), 4.65, 4.55 (bs, 2H), 3.94 (s, 3H), 3.39-3.28(m, bs, 4H), 2.47 (m, 4H), 2.25 (s, 3H), 1.71, 1.66 (s, 6H), mixture oftautomers.

Operating in an analogous way, the following compounds were obtained:

1H-Pyrrole-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(1H-pyrrole-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 10

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.54, 12.44 (s, 1H), 12.24 (s, 1H),11.73 (s, 1H), 10.85, 10.81 (s, 1H), 8.30 (bs, 1H), 7.93, 7.79 (d,J=8.78 Hz, 1H), 7.66 (m, 1H), 7.58 (m, 2H), 7.03 (m, 1H), 6.79-6.64 (m,2H), 6.21 (m, 1H), 4.64, 4.54 (s, 2H), 3.36-3.26 (m, 4H), 2.45 (m, 4H),2.22 (s, 3H), 1.68, 1.64 (s, 6H), mixture of tautomers.

2-Benzoylamino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=benzoylamino, R2=4-methyl-piperazin-1-yl], cpd. 22

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.89, 12.62 (s, 1H), 12.59, 12.33(s, 1H), 10.98, 10.91 (s, 1H), 8.39 (d, J2=2.44 Hz, 1H), 7.99, 7.85 (m,3H), 7.68 (m, 2H), 7.59 (m, 4H), 6.85, 6.75 (m, 1H), 4.72, 4.58 (m, 2H),3.35 (m, 4H), 2.48 (m, 4H), 2.25 (s, 3H), 1.70, 1.65 (s, 6H), mixture oftautomers.

Thiophene-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(thiophene-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 24

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.81, 12.60, 12.57, 12.31 (4 bs,2H), 10.93, 10.88 (2 bs, 1H), 8.24 (d, J=2.6 Hz, 1H), 8-7.7 (m, 2H),7.94 (dd, J1=4.9 Hz, J2=1 Hz, 1H), 7.68 (bt, 1H), 7.61 (bd, 2H), 7.26(dd, J1=3.8 Hz, J2=4.9 Hz, 1H), 6.83, 6.74 (2bd, 1H), 4.69, 4.56 (2bs,2H), 3.35 (m, 4H), 2.48 (bt, 4H), 2.25 (s, 4H), 1.70, 1.66 (2bs, 6H),mixture of tautomers.

5-Methyl-2H-pyrazole-3-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amidetrifluoroacetate [(I) Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=(5-methyl-2H-pyrazole-3-carbonyl)amino,R2=4-methyl-piperazin-1-yl], cpd. 31

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 13.11 (bs, 1H), 12.22 (bs, 1H),10.87 (bs, 1H), 9.75 (bs, 1H), 8.40 (d, J=2.4 Hz, 1H), 7.86 (d, J=8.9Hz, 1H), 7.7-7.6 (m, 3H), 6.83 (dd, J1=9.3 Hz, J2=2.1 Hz), 6.50 (s, 1H),4.60 (s, 1H), 4.02 (2bs, 2H), 3.57 (2bs, 2H), 3.25-3.05 (m, 4H), 2.89(s, 3H), 2.31 (s, 3H), 1.67 (s, 6H).

Thiazole-4-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(thiazole-4-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 34

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.8-12.2 (4bs, 2H), 10.84, 10.79(2bs, 1H), 9.21 (bs, 1H), 8.50 (d, J=1.8 Hz, 1H), 8.42, 8.39 (2bs, 1H),7.9-7.75 (2bd, 1H), 7.66 (bt, 1H), 7.61 (bd, 2H), 6.84-6.74 (2bd, 1H),4.66, 4.54 (2bs, 2H), 3.34 (m, 4H), 2.49 (m, 4H), 2.26 (s, 3H), 1.70,1.65 (2bs, 6H), mixture of tautomers.

3-Methyl-thiophene-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(3-methyl-thiophene-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl],cpd. 35

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.56, 12.31 (2bs, 1H), 12.14, 12.09(2bs, 1H), 10.92, 10.85 (2bs, 1H), 8.27 (d, J=2.4 Hz, 1H), 7.95 (bd,1H), 7.73 (d, J=5 Hz, 1H), 7.69 (bt, 1H), 7.6-7.55 (m, 2H), 7.09 (d, J=5Hz, 1H), 6.73 (d, 1H), 4.61, 4.53 (2bs, 2H), 3.3 (m, 4H), 2.57 (bs, 3H),2.48 (m, 4H), 2.25 (s, 3H), 1.70, 1.65 (2bs, 6H), mixture of tautomers.

2-[(3-Pyrrolidin-1-ylmethyl-benzoyl)amino]-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=(3-pyrrolidin-1-ylmethyl-benzoyl)amino], cpd. 67

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.54 (bs, 1H), 11.84 (bs, 1H),11.22 (bs, 1H), 8.50 (d, J=8.05 Hz, 1H), 7.94 (d, J=7.43 Hz, 1H), 7.88(s, 1H), 7.82 (d, J=7.68 Hz, 1H), 7.68-7.48 (m, 6H), 7.24 (m, 1H), 4.65(bs, 2H), 3.67 (s, 2H), 2.45 (m, bs, 4H), 1.70-1.61 (m, bs, 10H).

Tetrahydro-furan-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(tetrahydro-furan-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd.144

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.51, 12.04 (s, 1H), 12.15, 11.99(s, 1H), 10.78, 10.76 (s, 1H), 8.23 (m, bs, 1H), 7.86, 7.73 (d, J1=9.02Hz, 1H), 7.65 (m, 1H), 7.53 (m, 2H), 6.77, 6.67 (d, bs, J1=9.02 Hz, 1H),4.60, 4.53 (m, bs, 2H), 4.36 (dd, J1=8.66 Hz, J2=5.00 Hz, 1H), 4.02 (m,1H), 3.86 (m, 1H), 3.30-3.24 (m, 4H), 2.44 (m, bs, 4H), 2.29-2.20 (m,4H), 2.00-1.78 (m, 3H), 1.68, 1.64 (s, 6H), mixture of tautomers.

(S)-Tetrahydro-furan-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=((S)-tetrahydro-furan-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl],cpd. 1

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.51, 12.04 (s, 1H), 12.15, 11.99(s, 1H), 10.78, 10.76 (s, 1H), 8.23 (m, bs, 1H), 7.86, 7.73 (d, J1=9.02Hz, 1H), 7.65 (m, 1H), 7.53 (m, 2H), 6.77, 6.67 (d, bs, J1=9.02 Hz, 1H),4.60, 4.53 (m, bs, 2H), 4.36 (dd, J1=8.66 Hz, J2=5.00 Hz, 1H), 4.02 (m,1H), 3.86 (m, 1H), 3.30-3.24 (m, 4H), 2.44 (m, bs, 4H), 2.29-2.20 (m,4H), 2.00-1.78 (m, 3H), 1.68, 1.64 (s, 6H), mixture of tautomers.

(R)-Tetrahydro-furan-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=((R)-tetrahydro-furan-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl],cpd. 2

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.51, 12.04 (s, 1H), 12.15, 11.99(s, 1H), 10.78, 10.76 (s, 1H), 8.23 (m, bs, 1H), 7.86, 7.73 (d, J1=9.02Hz, 1H), 7.65 (m, 1H), 7.53 (m, 2H), 6.77, 6.67 (d, bs, J1=9.02 Hz, 1H),4.60, 4.53 (m, bs, 2H), 4.36 (dd, J1=8.66 Hz, J2=5.00 Hz, 1H), 4.02 (m,1H), 3.86 (m, 1H), 3.30-3.24 (m, 4H), 2.44 (m, bs, 4H), 2.29-2.20 (m,4H), 2.00-1.78 (m, 3H), 1.68, 1.64 (s, 6H), mixture of tautomers.

Tetrahydro-furan-3-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(tetrahydro-furan-3-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd.6

1H-NMR (500 MHz), δ (ppm, DMSO-d₆): 12.47, 12.13 (2bs, 1H), 11.56, 11.35(2bs, 1H), 10.74, 10.72 (2s, 1H), 8.00 (bs, 1H), 7.80, 7.69 (2d, 1H),7.61 (m, 1H), 7.56 (m, 2H), 6.73, 6.63 (2d, 1H), 4.55, 4.47 (2bs, 2H),3.90-3.62 (m, 4H), 3.23 (m, 4H), 3.13 (m, 1H), 2.40 (m, 4H), 2.18 (s,3H), 2.11 (m, 1H), 2.05 (m, 1H), 1.64, 1.59 (2s, 6H), mixture oftautomers.

(S)-1-Methyl-pyrrolidine-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=((S)-1-methyl-pyrrolidine-2-carbonyl)amino], cpd. 55

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.61, 12.20 (s, 1H), 11.69, 11.58(s, 1H), 11.14, 11.12 (s, 1H), 8.50 (d, J=8.24 Hz, 1H), 7.85, 7.78 (d,J=7.94 Hz, 1H), 7.72-7.51 (m, 4H), 7.24, 7.15 (m, 1H), 4.65, 4.56 (s,2H), 3.39-3.29 (m, 1H), 3.09 (m, 1H), 2.94 (m, 1H), 2.44-2.34 (m, 4H),2.21 (m, 1H), 1.82-1.65 (m, 8H), mixture of tautomers.

(S)-1-Methyl-pyrrolidine-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide{(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=[(S)-1-methyl-pyrrolidine-2-carbonyl]amino, R2=methoxy}, cpd. 56

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.56 (bs, 1H), 12.2-12.0 (m, 2H),10.93 (bs, 1H), 8.26 (m, 1H), 8.0-7.75 (m, 1H), 7.69 (m, 1H), 7.54 (m,2H), 6.9-6.65 (m, 1H), 4.64, 4.56 (2bs, 2H), 3.82 (bs, 1H), 3.11 (m,1H), 2.95 (m, 1H), 2.45-2.30 (m, 4H), 2.21 (m, 1H), 1.85-1.55 (m, 8H),mixture of tautomers.

Tetrahydro-pyran-4-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(tetrahydro-pyran-4-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd.7

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.52, 12.22 (s, 1H), 11.68, 11.47(s, 1H), 10.80, 10.76 (bs, 1H), 8.13 (s, 1H), 7.85, 7.73 (d, J=8.85 Hz,1H), 7.76 (m, 1H), 7.58 (m, 2H), 6.76, 6.66 (d, bs, J=8.85 Hz, 1H),4.59, 4.50 (s, 2H), 3.91 (m, 2H), 3.42-3.26 (m, 6H), 2.56 (m, 1H), 2.44(m, bs, 4H), 2.22 (s, 3H), 1.82 (m, bs, 2H), 1.67-1.63 (m, 8H), mixtureof tautomers.

Tetrahydro-pyran-4-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(tetrahydro-pyran-4-carbonyl)amino, R2=dimethylamino], cpd. 69

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.50, 12.19 (s, 1H), 11.87, 11.64(s, 1H), 10.70, 10.67 (s, 1H), 7.97 (bs, 1H), 7.86, 7.73 (d, J=9.14 Hz,1H), 7.65 (m, 1H), 7.58 (m, 2H), 6.50, 6.41 (m, bs, 1H), 4.59, 4.50 (s,2H), 3.91 (m, 2H), 3.40 (m, 2H), 3.00, 2.99 (s, 6H), 2.57 (m, 1H), 1.83(m, 2H), 1.71-1.60 (m, 8H), mixture of tautomers.

Tetrahydro-pyran-4-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,121=(Tetrahydro-pyran-4-carbonyl)amino, R2=morpholin-4-yl], cpd. 70

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.54, 12.24, 11.68, 11.46 10.83,10.80 (6bs, 3H), 8.15 (bd, J=2.3 Hz, 1H), 7.90, 7.88, 7.78, 7.76 (2bd,1H), 7.67 (bt, 1H), 7.60 (bd, 2H), 6.85-6.65 (m, 1H), 4.61, 4.52 (2bs,2H), 3.92 (m, 2H), 3.75 (m, 4H), 3.41 (m, 2H), 3.26 (m, 4H), 2.58 (m,1H), 1.9-1.6 (m, 10H), mixture of tautomers.

5-Methyl-isoxazole-4-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(5-methyl-isoxazole-4-carbonyl)amino, R2=4-methyl-piperazin-1-yl],cpd. 23

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.36, 12.13 (bs, 1H), 10.63, 10.56(bs, 1H), 9.58 (bs, 1H), 8.25 (bs, 1H), 7.63 (m, 3H), 7.39 (d, J=8.78Hz, 1H), 6.60 (m, bs, 1H), 4.71, 4.57 (bs, 2H), 3.91-3.01 (m, bs, 8H),2.85 (s, 3H), 1.96 (s, 3H), 1.64 (bs, 6H), mixture of tautomers.

1H-Pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-fluoro-phenyl}-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(1H-pyrrole-2-carbonyl)amino, R2=fluoro], cpd. 39

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.63, 12.39 (s, 1H), 12.06 (s, 1H),11.92, 11.81 (s, 1H), 11.26, 11.20 (s, 1H), 8.43, 8.40 (d, J2=2.68 Hz,1H), 8.08, 7.97 (m, 1H), 7.67 (m, 1H), 7.58 (m, 2H), 7.09, 6.99 (m, 1H),7.06 (m, 1H), 6.82, 6.75 (m, 1H), 6.23 (m, 1H), 4.66, 4.54 (s, 2H),1.69-1.64 (s, 6H), mixture of tautomers.

1H-Pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(1H-pyrrole-2-carbonyl)amino, R2=methoxy], cpd. 40

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.62, 12.34, 12.30, 12.06, 11.87,11.07, 11.03 (7bs, 4H), 8.32 (m, 1H), 8.1-7.9 (m, 1H), 7.69 (bt, 1H),7.60 (bd, 2H), 7.06 (m, 1H), 6.85-6.65 (m, 2H), 6.25 (m, 1H), 4.68, 4.67(2bs, 2H), 3.86 (bs, 3H), 1.72, 1.67 (2bs, 6H), mixture of tautomers.

1-Methyl-1H-pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(1-methyl-1H-pyrrole-2-carbonyl)amino, R2=morpholin-4-yl], cpd. 59

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.57, 12.46, 12.25 (3bs, 2H),10.90, 10.84 (2bs, 1H), 8.32 (m, 1H), 8.0-7.80 (m, 1H), 7.68 (m, 1H),7.59 (m, 2H), 7.09 (m, 1H), 6.90-6.65 (m, 2H), 6.16 (m, 1H), 4.66, 4.56(2bs, 2H), 3.94 (bs, 3H), 3.78 (m, 4H), 3.35-3.25 (m, 4H), 1.71, 1.66(2bs, 6H), mixture of tautomers.

1H-Pyrrole-2-carboxylic acid[2-(5-benzenesulfonyl-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl)-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=phenyl,R1=(1H-pyrrole-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 102

1H-NMR (600 MHz), δ (ppm, DMSO-d₆): 12.49, 12.44, 12.21, 12.16 (4s, 2H),11.73 (s, 1H), 10.81, 10.77 (2s, 1H), 8.27 (m, 1H), 7.93-7.73 (m, 3H),7.65 (m, 1H), 7.58 (m, 2H), 7.02 (m, 1H), 6.77-6.61 (m, 2H), 6.23 (m,1H), 4.53, 4.42 (2s, 2H), 3.3 (m, 4H), 2.44 (m, 4H), 2.21 (bs, 3H),1.67, 1.61 (2s, 6H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-dimethylamino-acetylamino)-benzamide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=2-dimethylamino-acetylamino], cpd. 145

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.61, 12.24 (2bs, 1H), 11.57 (bs,1H), 11.14 (bs, 1H), 8.49 (m, 1H), 7.84 (m, 1H), 7.68 (m, 1H), 7.59-7.51(m, 3H), 7.16 (m, 1H), 4.66, 4.58 (2bs, 2H), 3.08 (s, 2H), 2.30 (s, 6H),1.73, 1.67 (2bs, 6H), mixture of tautomers.

Example 9 Preparation of5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-{2-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=B=D=E=CH,R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino]

A solution of 1H-pyrrole-2-carboxylic acid (0.8 g, 7.2 mmol) in drydichloromethane (10 mL), oxalyl chloride (5.8 mL, 68.5 mmol) and twodrops of N,N-dimethylformamide was stiffed at room temperatureovernight. The solvent was evaporated under reduced pressure, theresidue dissolved in dry dichloromethane (10 mL) and added to a solutionof3-(2-amino-benzoylamino)-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (2.5 g, 4.8 mmol), N,N-diisopropylethylamine (4 eq.,3.3 mL, 19.6 mmol) in dry dichloromethane (60 mL). The reaction mixturewas stirred at room temperature overnight, washed with 1N HCl (50 mL),saturated sodium hydrogenocarbonate (50 mL), brine (50 mL) and driedover sodium sulfate. The solvent was removed under vacuum and the cruderesidue purified by flash chromatography on silica gel, usinghexane-ethyl acetate 6:4 as eluant, yielding the title compound ascolourless solid (2.6 g, 88% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.84 (s, 1H), 11.09 (s, 1H), 10.89(s, 1H), 8.32 (d, J=8.24 Hz, 1H), 7.81 (d, bs, J=7.94 Hz, 1H), 7.70-7.59(m, 4H), 7.29 (m, 1H), 7.02 (m, 1H), 6.84 (m, 1H), 6.22 (m, 1H), 4.71(s, 2H), 4.38 (q, J=7.02 Hz, 2H), 1.68 (s, 6H), 1.31 (t, J=7.02 Hz, 3H).

Operating in an analogous way, the following compounds were obtained:

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-{2-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=B=D=E=CH,R=3,5-difluorophenyl, R1=(1-methyl-1H-pyrrole-2-carbonyl)amino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.09 (s, 1H), 10.88 (s, 1H), 8.32(d, bs, J=8.05 Hz, 1H), 7.83 (dd, J1=8.05 Hz, J2=1.34 Hz, 1H), 7.72-7.59(m, 4H), 7.31 (ddd, bs, J1=8.29 Hz, J2=7.50 Hz, 1H), 7.09 (m, 1H), 6.89(dd, J1=4.02 Hz, J2=1.70 Hz, 1H), 6.15 (dd, J1=4.02 Hz, J2=2.56 Hz, 1H),4.71 (s, 2H), 4.40 (q, J=7.07 Hz, 2H), 3.88 (s, 3H), 1.70 (s, 6H), 1.33(t, J=7.07 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-{4-morpholin-4-yl-2-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino,R2=morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.88 (s, 1H), 11.77 (s, 1H), 10.75(s, 1H), 8.22 (d, J2=2.57 Hz, 1H), 7.67 (m, 1H), 7.65 (d, J1=9.02 Hz,1H), 7.61 (m, 2H), 7.04 (m, 1H), 6.83 (dd, J1=9.02 Hz, J2=2.57 Hz, 1H),6.77 (m, 1H), 6.23 (m, 1H), 4.72 (s, 2H), 4.41 (q, J=7.08 Hz, 2H), 3.75(m, 4H), 3.33-3.24 (m, 4H), 1.68 (s, 6H), 1.33 (t, J=7.08 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-{4-dimethylamino-2-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=dimethylamino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.09 (bs, 1H), 11.82 (bs, 1H),10.73 (s, 1H), 8.10 (d, J2=2.57 Hz, 1H), 7.70 (m, 1H), 7.65-7.62 (m,3H), 7.06 (m, 1H), 6.78 (m, 1H), 6.59 (dd, J1=9.15 Hz, J2=2.57 Hz, 1H),6.25 (m, 1H), 4.74 (s, 2H), 4.44 (q, J=7.07 Hz, 2H), 3.06 (s, 6H), 1.70(s, 6H), 1.36 (t, J=7.07 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-{2-fluoro-6-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylicacid ethyl ester [(VII) Q=ethyl, Ra═Rb=methyl, A=B=D=CH, E=CR2,R=3,5-difluorophenyl, R1=(1H-pyrrole-2-carbonyl)amino, R2=fluoro]

1H-NMR (400 MHz), δ (ppm, CDCl₃): 11.97 (s, 1H), 9.34 (s, 1H), 9.08 (d,1H), 8.64 (d, 1H), 7.50 (m, 3H), 7.03 (m, 2H), 6.88 (m, 2H), 6.42 (s,1H), 4.79 (s, 2H), 4.52 (q, 2H), 1.97 (s, 6H), 1.47 (t, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-(2-{[1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl]-amino}-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester {(VII) Q=ethyl, Ra═Rb=methyl, A=B=D=E=CH,R=3,5-difluorophenyl,R1=[1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl]-amino}

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.81 (s, 1H), 10.74 (s, 1H), 8.02(dd, J1=2.20 Hz, J2=1.70 Hz, 1H), 7.96 (m, 3H), 7.81 (dd, J1=7.80 Hz,J2=1.46 Hz, 1H), 7.70-7.59 (m, 4H), 7.51-7.46 (m, 3H), 7.36 (m, 1H),6.74 (dd, J1=3.29 Hz, J2=1.70 Hz, 1H), 4.69 (bs, 2H), 4.31 (q, J=7.07Hz, 2H), 2.41 (s, 3H), 1.68 (s, 6H), 1.26 (t, J=7.07 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-3-(4-dimethylamino-2-{[1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl]-amino}-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester {(VII) Q=ethyl, Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl,R1=[1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl]-amino,R2=dimethylamino}

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.77 (s, 1H), 10.73 (s, 1H), 7.96(d, J=8.42 Hz, 1H), 7.89 (m, 1H), 7.86 (d, J2=2.56 Hz, 1H), 7.65-7.61(m, 3H), 7.49-7.47 (m, 1H), 7.47 (d, J=8.42 Hz, 2H), 6.70 (m, 1H), 6.59(dd, J1=9.02 Hz, J2=2.56 Hz, 1H), 4.73 (s, 2H), 4.38 (q, J=7.08 Hz, 1H),3.02 (s, 6H), 2.38 (s, 3H), 1.66 (s, 6H), 1.30 (t, J=7.08 Hz, 3H).

5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-3-{2-[(pyridine-2-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester [(VII) Q=Ethyl, Ra═Rb=methyl, A=B=D=E=CH,R=3,5-difluorophenyl, R1=(pyridine-2-carbonyl)-amino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.7 (bs, 1H), 10.9 (bs, 1H), 8.69(m, 2H), 8.20 (d, 1H), 8.11 (t, 1H), 7.89 (d, J=7.94 Hz, 1H), 7.70-7.59(m, 4H), 7.24 (t, 1H), 4.75 (s, 2H), 4.38 (q, J=7.02 Hz, 2H), 1.68 (s,6H), 1.31 (t, J=7.02 Hz, 3H).

Example 10 Preparation of 1H-pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=(1H-pyrrole-2-carbonyl)amino], cpd. 36

A solution of5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-{2-[(1H-pyrrole-2-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (1.2 g, 1.9 mmol) and triethylamine (3 eq., 0.82 mL,5.9 mmol) in dichloromethane-MeOH 1:1 (40 mL) was stirred overnight atroom temperature. The solvent was evaporated under reduced pressure andthe residue purified by flash chromatography, using ethyl acetate-hexane6:4 as eluant, to yield the title compound as colourless solid (0.92 g,90% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.62, 12.38 (bs, 1H), 11.85 (bs,1H), 11.70, 11.45 (bs, 1H), 11.21 (s, 1H), 8.53 (d, J=8.29 Hz, 1H),7.95, 7.88 (m, bs, 1H), 7.67 (m, 1H), 7.58 (m, 3H), 7.24-7.15 (m, bs,1H), 7.02 (m, 2H), 6.82, 6.76 (m, bs, 1H), 6.22 (m, 1H), 4.67, 4.55 (bs,2H), 1.7 (bs, 6H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl, R1=amino]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.47, 12.11 (s, 1H), 10.56 (s, 1H),7.61 (m, 3H), 7.2 (bs, 1H), 6.77 (bs, 1H), 6.59-6.43 (bs, 2H), 4.62,4.55 (bs, 2H), 1.67, 1.64 (bs, 6H), mixture of tautomers.

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino,R2=morpholin-4-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.35, 11.96 (bs, 1H), 10.24 (s,1H), 7.65-7.55 (m, 4H), 6.54 (bs, 2H), 6.22 (m, bs, 1H), 6.16 (d, J=1.83Hz, 1H), 4.53 (bs, 2H), 3.70 (m, 4H), 3.13 (m, 4H), 1.62 (s, 6H),mixture of tautomers.

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino,R2=4-methyl-piperazin-1-yl]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.37, 11.99 (bs, 1H), 10.25 (bs,1H), 7.67-7.59 (m, 4H), 6.55 (bs, 2H), 6.30-6.15 (m, bs, 2H), 4.56 (bs,2H), 3.20 (m, bs, 4H), 2.43 (m, 4H), 2.23 (s, 3H), 1.65 (bs, 6H),mixture of tautomers.

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-methoxy-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino,R2=methoxy]

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.41, 12.03 (2s, 1H), 10.40, 10.37(2s, 1H), 7.72-7.57 (m, 4H), 6.73, 6.67 (2bs, 2H), 6.34-6.09 (m, 2H),4.61, 4.53 (2bs, 2H), 3.75, 3.73 (2s, 3H), 1.67, 1.63 (2s, 6H), mixtureof tautomers.

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-dimethylamino-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl, R1=amino,R2=dimethylamino]

ESI (+) MS: m/z 491 (MH⁺).

2-Amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-6-fluoro-benzamide[(I) Ra═Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl, R1=amino,R2=fluoro]

ESI (+) MS: m/z 466 (MH⁺).

1-Methyl-1H-pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=(1-methyl-1H-pyrrole-2-carbonyl)amino], cpd. 58

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.64, 12.38 (s, 1H), 11.68, 11.44(s, 1H), 11.22 (bs, 1H), 8.52, 8.47 (d, J=8.41 Hz, 1H), 7.96, 7.82 (d,bs, J=8.17 Hz, 1H), 7.71-7.53 (m, 4H), 7.24, 7.16 (m, 1H), 7.09 (bs,1H), 6.88, 6.83 (m, bs, 1H), 6.26, 6.16 (dd, J1=3.65 Hz, J2=2.43 Hz,1H), 4.67, 4.54 (s, 2H), 3.98, 3.92 (s, 3H), 1.71, 1.66 (s, 6H), mixtureof tautomers.

1H-Pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(1H-pyrrole-2-carbonyl)amino, R2=morpholin-4-yl], cpd. 38

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.57, 12.46 (2s, 1H), 12.28, 12.25(2s, 1H), 11.76 (s, 1H), 10.90, 10.86 (2s, 1H), 8.33 (m, 1H), 7.98, 7.84(2m, 1H), 7.69 (m, 1H), 7.61 (m, 2H), 7.05 (m, 1H), 6.86-6.66 (m, 2H),6.24 (m, 1H), 4.67, 4.57 (2s, 2H), 3.77 (m, 4H), 3.30 (m, 4H), 1.71,1.66 (2s, 6H), mixture of tautomers.

1H-Pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(1H-pyrrole-2-carbonyl)amino, R2=dimethylamino], cpd. 37

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.59, 12.37 (bs, 1H), 12.51, 12.20(bs, 1H), 11.75 (s, 1H), 10.74 (s, 1H), 8.13 (d, J2=2.44 Hz, 1H), 7.92,7.80 (m, bs, 1H), 7.66 (m, 1H), 7.57 (m, 2H), 7.02 (m, 1H), 6.78, 6.73(m, bs, 1H), 6.49, 6.43 (m, bs, 1H), 6.21 (m, 1H), 4.64, 4.55 (bs, 2H),3.01 (s, 6H), 1.68, 1.65 (bs, 6H), mixture of tautomers.

1H-Pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-3-fluoro-phenyl}-amide[(I) Ra═Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl,R1=(1H-pyrrole-2-carbonyl)amino, R2=fluoro], cpd. 123

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.58 (s, 1H), 11.84 (s, 1H), 11.13(s, 1H), 10.19 (s, 1H), 7.96 (m, 1H), 7.68 (m, 1H), 7.57 (m, 3H), 7.10(m, 1H), 7.02 (m, 1H), 6.79 (m, 1H), 6.20 (m, 1H), 4.65 (bs, 2H), 1.70(bs, 6H).

Pyridine-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=(pyridine-2-carbonyl)amino], cpd. 75

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.62, 12.47 (s, 1H), 12.59, 12.39(s, 1H), 11.23 (s, 1H), 8.72-8.67 (m, 2H), 8.21 (ddd, J1=7.68 Hz,J2=2.07 Hz, J3=0.98 Hz, 1H), 8.10 (ddd, J1=8.53 Hz, J2=7.68 Hz, J3=1.59Hz, 1H), 7.90, 7.86 (m, bs, 1H), 7.73-7.57 (m, 5H), 7.32, 7.24 (m, bs,1H), 4.75, 4.59 (s, 2H), 1.72, 1.67 (s, 6H), mixture of tautomers.

Example 11 Preparation of 1H-pyrrole-3-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=(1H-pyrrole-3-carbonyl)amino], cpd. 46

A solution of5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-(2-{[1-(toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl]-amino}-benzoylamino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (1.1 g, 1.4 mmol) in 1,4-dioxane (30 mL), was treatedwith 1N NaOH (9 mL) at 60° C. for 8 hours. The reaction mixture wasdiluted with dichloromethane (50 mL) and then washed with 1N HCl (20mL), saturated sodium hydrogenocarbonate (20 mL), brine (20 mL), driedover sodium sulfate and evaporated to dryness. The crude material waspurified by flash chromatography on silica gel, usingdichloromethane-MeOH 95:5 as eluant, to yield the title compound as paleyellow solid (0.6 g, 77% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.61, 12.39 (s, 1H), 11.50 (s, 1H),11.45 (s, 1H), 11.29, 11.18 (s, 1H), 8.57 (d, J1=8.24 Hz, 1H), 7.92,7.86 (m, bs, 1H), 7.67-7.52 (m, 4H), 7.42 (m, bs, 1H), 7.20, 7.12 (m,bs, 1H), 6.87 (m, bs, 1H), 6.49 (m, bs, 1H), 4.67, 4.54 (s, 2H), 1.69,1.64 (s, 6H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

1H-Pyrrole-3-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(1H-pyrrole-3-carbonyl)amino, R2=dimethylamino], cpd. 47

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40 (bs, 1H), 12.28 (bs, 1H),11.41 (s, 1H), 10.67 (bs, 1H), 8.18 (d, J2=2.68 Hz, 1H), 7.84 (m, bs,1H), 7.64 (m, 1H), 7.58 (m, 2H), 7.37 (m, 1H), 6.86 (m, 1H), 6.50 (m,1H), 6.41 (d, bs, J1=8.90 Hz, 1H), 4.60 (s, 2H), 3.00 (s, 6H), 1.66 (s,6H).

Example 12 Preparation of 1H-pyrrole-3-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(1H-pyrrole-3-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 11

1-(Toluene-4-sulfonyl)-1H-pyrrole-3-carbonyl chloride (2.4 eq., 2 mmol)was added to the mixture of2-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide(0.45 g, 0.82 mmol) and N,N-diisopropylethylamine (6 eq., 0.86 mL, 4.92mmol) in dry dichloromethane (15 mL), maintained under stirring at roomtemperature. After 24 hours, methanol (100 mL) was added and stirringwas continued for 70 hours. The mixture was then evaporated to dryness,dissolved with 1,4-dioxane (30 mL), treated with 1N NaOH (10 mL) andwater (20 mL) stirred at room temperature for 20 hours and diluted withdichloromethane-water 1:1 (200 mL). The organic layer was separated,washed with brine, dried over sodium sulfate and evaporated to dryness.The title compound was obtained after purification on silica gel, usingdichloromethane-methanol-30% NH₄OH 100:10:1 as eluant, as beige solid(0.150 g, 29% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.53, 12.24 (s, 1H), 12.21, 12.05(s, 1H), 11.42 (s, 1H), 10.80, 10.77 (s, 1H), 8.38, 8.37 (bs, 1H), 7.90,7.77 (d, J1=9.15 Hz, 1H), 7.64 (m, 1H), 7.58 (m, 2H), 7.37 (m, 1H), 6.86(m, 1H), 6.72, 6.63 (d, bs, J1=9.15 Hz, 1H), 6.51, 6.48 (m, bs, 1H),4.65, 4.54 (s, 2H), 3.39-3.23 (m, 4H), 2.44 (m, 4H), 2.22 (s, 3H), 1.68,1.63 (s, 6H), mixture of tautomers.

Example 13 Preparation of 3H-imidazole-4-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(3H-imidazole-4-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 14

Oxalyl chloride (4.15 eq., 0.186 mL, 2.2 mmol) was added to the solutionof 1-trityl-1H-imidazole-4-carboxylic acid (4 eq., 0.76 g, 2.14 mmol),N,N-diisopropylethylamine (17 eq., 1.3 mL, 8.8 mmol) and4-(N,N-dimethylamino)pyridine (4.15 eq., 0.27 g, 2.2 mmol) in drydichloromethane (10 mL), maintained under stirring at room temperature.After about 10 minutes3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester hydrochloride (0.35 g, 0.53 mmol) was added andstirring was continued for 6 hours. The mixture was diluted withdichloromethane (100 mL), washed with saturated sodiumhydrogenocarbonate (100 mL), dried over sodium sulfate and evaporated todryness. The resulting dark brown oil was treated with 4N HCl in1,4-dioxane (10 mL) at room temperature for 20 hours, evaporated, addedwith triethylamine (5 mL) and methanol (15 mL) and stirred for about 4hours. After removal of the solvents, the crude material was purified byflash chromatography on silica gel, using dichloromethane-methanol-30%NH₄OH 100:10:1 as eluant, to give the title compound as colourless solid(0.09 g, 26% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.61 (s, 1H), 12.48 (s, 1H), 12.20(s, 1H), 10.73 (s, 1H), 8.38 (m, bs, 1H), 7.79-7.72 (m, 3H), 7.76-7.56(m, 3H), 6.70 (m, bs, 1H), 4.62, 4.52 (bs, 2H), 3.31-3.24 (m, 4H), 2.45(m, 4H), 2.22 (s, 3H), 1.67-1.64 (bs, 6H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

1H-Imidazole-4-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=(1H-imidazole-4-carbonyl)amino], cpd. 57

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.67, 12.38 (s, 1H), 12.58 (s, 1H),11.62, 11.59 (s, 1H), 11.14 (s, 1H), 8.65, 8.60 (d, J=8.38 Hz, 1H),7.82-7.52 (m, 7H), 7.22, 7.14 (m, 1H), 4.67, 4.53 (s, 2H), 1.69, 1.64(s, 6H), mixture of tautomers.

Example 14 Preparation of piperidine-3-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(piperidine-3-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 4

A solution of N-FMOC-piperidine-3-carbonyl chloride (5 eq., 0.85 g, 2.3mmol) in dry dichloromethane (5 mL) was added to the solution of3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester hydrochloride (0.30 g, 0.46 mmol) andN,N-diisopropylethylamine (10 eq., 0.80 mL, 4.6 mmol) in drydichloromethane (10 mL), maintained under stiffing at room temperature.After 20 hours, piperidine (5 mL) and methanol (20 mL) were added to thereaction mixture and stirring was continued for 70 hours at roomtemperature. After evaporation of the solvent, the crude material waspurified by flash chromatography on silica gel, usingdichloromethane-methanol-30% NH₄OH 100:10:1 as eluant, to yield thetitle compound as yellow solid (0.126 g, 41% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.41 (bs, 1H), 11.59 (bs, 1H),10.78 (bs, 1H), 8.10 (d, J2=2.56 Hz, 1H), 7.79, 7.70 (d, bs, J1=8.78 Hz,1H), 7.64 (m, 1H), 7.57 (m, 2H), 6.68 (m, bs, 1H), 4.59, 4.55 (bs, 2H),3.27-3.22 (m, 4H), 3.18 (m, 1H), 3.09 (m, 1H), 2.86 (m, 1H), 2.66 (m,1H), 2.55-2.46 (m, 1H), 2.42 (m, 4H), 2.21 (s, 3H), 1.95 (m, 2H),1.68-1.56 (m, 8H), 1.43 (m, 2H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

Piperidine-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(piperidine-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 3

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.48, 12.36 (bs, 1H), 12.10, 11.89(bs, 1H), 10.72 (bs, 1H), 8.21 (d, J2=2.19 Hz, 1H), 7.76 (m, bs, 1H),7.65 (m, 1H), 7.54 (m, 2H), 6.84, 6.69 (m, bs, 1H), 4.65, 4.41 (bs, 2H),3.25 (m, 4H), 3.17 (m, 1H), 2.91 (m, 1H), 2.57 (m, 1H), 2.43 (m, 4H),2.21 (m, 3H), 1.81 (m, 1H), 1.66 (m, bs, 7H), 1.50-1.29 (m, 4H), mixtureof tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methylamino-acetylamino)-benzamide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=2-methylamino-acetylamino], cpd. 146

ESI (+) MS: m/z 519 (MH⁺).

(S)-Pyrrolidine-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=(S)-(pyrrolidine-2-carbonyl)amino], cpd. 147

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.56, 12.23 (2bs, 1H), 11.67 (bs,1H), 11.06 (bs, 1H), 8.46 (m, 1H), 7.79-7.44 (m, 5H), 7.12 (m, 1H),4.71-4.46 (m, 2H), 3.73 (m, 1H), 2.94 (m, 1H), 2.81 (m, 1H), 2.06 (m,1H), 1.76 (m, 1H), 1.72-1.58 (m, 8H), mixture of tautomers.

(S)-Pyrrolidine-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(S)-(pyrrolidine-2-carbonyl)amino, R2=methoxy], cpd. 148

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.54, 12.12 (2bs, 2H), 10.90 (bs,1H), 8.24 (m, 1H), 7.83 (m, 1H), 7.68 (m, 1H), 7.58 (m, 2H), 6.84-6.65(m, 2H), 4.71-4.48 (m, 2H), 3.81 (s, 3H), 3.76 (m, 1H), 2.98 (m, 1H),2.86 (m, 1H), 2.08 (m, 1H), 1.78 (m, 1H), 1.74-1.55 (m, 8H), mixture oftautomers.

Example 15 Preparation of pyridine-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(pyridine-2-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 19

Oxalyl chloride (4 eq., 0.213 mL, 2.52 mmol) was slowly added to thesolution of picolinic acid (4 eq., 0.31 g, 2.52 mmol),N,N-diisopropylethylamine (16 eq., 1.7 6 mL, 10.1 mmol) and4-(N,N-dimethylamino)pyridine (4 eq., 0.31 g, 2.52 mmol) in drydichloromethane (10 mL), maintained under magnetic stirring at 0° C.After 5 minutes3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester hydrochloride (0.42 g, 0.63 mmol) was added at 0° C.The mixture was allowed to warm to room temperature and stirring wascontinued for 4 hours. After evaporation of the solvent, the mixture wasdiluted with dichloromethane (100 mL), washed with saturated sodiumhydrogenocarbonate, dried over sodium sulfate, evaporated to dryness andtreated with triethylamine (5 mL) and methanol (20 mL) at roomtemperature for 20 hours. After removal of the solvent, the crudematerial was purified by flash chromatography on silica gel, usingdichloromethane-methanol-30% NH₄OH 100:10:1 as eluant. The solid thusobtained was washed with methanol (5 mL) and then diethyl ether,filtered and dried to yield the title compound as white solid (0.120 g,29% yield).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 13.19, 13.06 (s, 1H), 12.51, 12.18(s, 1H), 10.83, 10.79 (s, 1H), 8.65 (m, 1H), 8.43 (m, 1H), 8.17, 8.15(m, 1H), 8.07 (ddd, J1=8.41 Hz, J2=7.68 Hz, J3=1.70 Hz, 1H), 7.85, 7.76(m, 1H), 7.69-7.61 (m, 2H), 7.57 (m, 2H), 6.82, 6.73 (m, 1H), 4.70, 4.56(s, 2H), 3.35-3.29 (m, 4H), 2.46 (m, 4H), 2.23 (s, 3H), 1.69, 1.64 (s,6H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

N-[2-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-isonicotinamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(pyridine-4-carbonyl)amino, R2=4-methyl-piperazin-1-yl], cpd. 21

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 13.0-12.2 (4bs, 2H), 10.97 (bs, 1H),8.84 (m, 2H), 8.30 (d, J=2.7 Hz, 1H), 7.99 (bs, 1H), 7.88 (m, 2H),7.70-7.55 (m, 3H), 6.90-6.75 (2bs, 1H), 4.75-4.50 (2bs, 2H), 3.86 (m,4H), 2.48 (m, 4H), 2.26 (s, 3H), 1.68 (s, 6H), mixture of tautomers.

Example 16 Preparation ofN-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-methoxy-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=tetrahydro-pyran-4-ylamino, R2=methoxy], cpd. 81

To a mixture of2-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-methoxy-benzamide(400 mg, 1.05 mmol), tetramethylammonium triacetoxyborohydride (413 mg,1.57 mmol, 1.5 eq), trifluoroacetic acid (1.5 mL) and dichloromethane(10 mL), tetrahydro-pyran-4-one (0.116 mL, 1.26 mmol, 1.2 eq) was added.The reaction mixture was stirred at room temperature for 30 min., thendiluted with dichloromethane (100 mL), washed with saturated sodiumhydrogenocarbonate (100 mL), dried over sodium sulfate and evaporated todryness. The crude was purified by flash chromatography, usingdichloromethane-ethyl acetate 1/1 as eluant, affording the titlecompound as white solid (358 mg).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.44, 12.15 (2s, 1H), 10.47 (bs,1H), 8.11 (m, 1H), 7.80-7.57 (m, 4H), 6.31-6.14 (m, 2H), 4.57, 4.50 (2s,2H), 3.85 (m, 2H), 3.81, 3.79 (2s, 3H), 3.67 (m, 1H), 3.51 (m, 2H), 1.97(m, 2H), 1.68, 1.63 (2s, 6H), 1.41 (m, 2H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 95

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.08 (s, 1H), 10.31 (s, 1H),8.15 (m, bs, 1H), 7.70-7.58 (m, bs, 4H), 6.24 (m, bs, 1H), 6.12 (bs,1H), 4.56, 4.51 (bs, 2H), 3.85 (m, 2H), 3.70 (m, bs, 1H), 3.52 (m, 2H),3.27 (m, 4H), 2.45 (m, 4H), 2.24 (s, 3H), 1.96 (m, bs, 2H), 1.66, 1.64(bs, 6H), 1.39 (m, bs, 2H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=tetrahydro-pyran-4-ylamino, R2=morpholin-4-yl], cpd. 80

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40, 12.10 (s, 1H), 10.33 (s, 1H),8.15 (m, bs, 1H), 7.73-7.60 (m, bs, 4H), 6.28, 6.18 (m, bs, 1H), 6.14(m, bs, 1H), 4.56, 4.50 (m, bs, 2H), 3.85 (m, 2H), 3.74 (m, 5H), 3.52(m, 2H), 3.23 (m, 4H), 1.96 (m, bs, 2H), 1.67, 1.63 (bs, 6H), 1.41 (m,bs, 2H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=tetrahydro-pyran-4-ylamino], cpd. 78

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.50, 12.23 (s, 1H), 10.71, 10.68(s, 1H), 7.77-7.58 (m, 5H), 7.84 (m, 1H), 6.86 (m, 1H), 6.62 (m, 1H),4.59, 4.51 (s, 2H), 3.87 (m, 2H), 3.65 (bs, 1H), 3.50 (m, 2H), 1.96 (m,2H), 1.69, 1.64 (s, 6H), 1.42 (m, 2H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-dimethylamino-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=tetrahydro-pyran-4-ylamino, R2=dimethylamino], cpd. 79

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.36, 12.05 (2bs, 1H), 10.22 (bs,1H), 8.22 (m, 1H), 7.65 (m, 1H), 7.60 (m, 2H), 6.1-6.0 (m, 1H), 5.87 8m,1H), 4.60-4.45 (m, 2H), 3.90-3.80 (m, 2H), 3.68 (m, 1H), 3.52 (m, 2H),2.98 (bs, 6H), 1.99 (m, 2H), 1.70-1.60 (m, 6H), 1.50-1.35 (m, 2H),mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl,R1=tetrahydro-pyran-4-ylamino, R2=fluoro], cpd. 124

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.51, 12.32 (2bs, 1H), 10.89, 10.76(2bs, 1H), 7.71-7.57 (m, 3H), 7.26 (m, 1H), 6.70-6.61 (m, 1H), 6.52-6.32(m, 1H), 6.12 (m, 1H), 4.63, 4.52 (2s, 2H), 3.85 (m, 2H), 3.61 (m, 1H),3.46 (m, 2H), 1.91 (m, 2H), 1.69, 1.65 (2s, 6H), 1.42 (m, 2H), mixtureof tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-isobutylamino-4-(4-methyl-piperazin-1-yl)-benzamidehydrochloride [(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=isobutylamino, R2=4-methyl-piperazin-1-yl], cpd. 90

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.42 (s, 1H), 10.37 (bs, 1H), 7.72(d, J1=9.03 Hz, 1H), 7.66 (m, 1H), 7.57 (m, 2H), 6.27 (dd, J1=9.03 Hz,J2=2.20 Hz, 1H), 6.10 (d, J2=2.20 Hz, 1H), 4.52 (s, 2H), 4.02 (m, bs,2H), 3.12 (m, bs, 6H), 3.00 (d, J=6.71 Hz, 2H), 2.85, 2.84 (d, J=4.5 Hz,3H), 1.91 (m, 1H), 1.66 (s, 6H), 1.00 (d, J=6.70 Hz, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(furan-2-ylmethyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzamidehydrochloride [(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,121=(furan-2-ylmethyl)-amino, R2=4-methyl-piperazin-1-yl], cpd. 93

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.43 (s, 1H), 10.26 (bs, 1H), 8.36(bs, 1H), 7.70 (d, J1=9.02 Hz, 1H), 7.63 (m, 1H), 7.58 (m, 2H), 7.57 (m,1H), 6.41 (dd, J1=3.17 Hz, J2=1.83 Hz, 1H), 6.36 (dd, bs, J1=3.17 Hz,1H), 6.29 (dd, bs, J1=9.02 Hz, J2=2.20 Hz, 1H), 6.24 (d, J2=2.20 Hz,1H), 4.52 (s, 2H), 4.43 (s, 2H), 4.00 (m, 2H), 3.48 (m, 2H), 3.10 (m,4H), 2.81 (d, J=4.4 Hz, 3H), 1.62 (s, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(1H-imidazol-2-ylmethyl)-amino]-4-(4-methyl-piperazin-1-yl)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(1H-imidazol-2-ylmethyl)-amino, R2=4-methyl-piperazin-1-yl], cpd. 94

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40, 12.04 (bs, 1H), 11.93 (bs,1H), 10.38, 10.32 (bs, 1H), 8.39 (t, J=5.37 Hz, 1H), 7.70-7.56 (m, 4H),7.04 (bs, 1H), 6.84 (bs, 1H), 6.31-6.14 (m, bs, 2H), 4.55 (bs, 2H), 4.38(d, J=J=5.37 Hz, 2H), 3.24 (m, 4H), 2.41 (m, 4H), 2.22 (s, 3H), 1.65(bs, 6H), mixture of tautomers.

2-Benzylamino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=benzylamino, R2=4-methyl-piperazin-1-yl], cpd. 96

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40, 12.05 (bs, 1H), 10.34 (bs,1H), 8.49 (bs, 1H), 7.73-7.56 (m, 4H), 7.40-7.34 (m, 4H), 7.27 (m, 1H),6.23 (m, bs, 1H), 6.04 (m, bs, 1H), 4.54 (m, bs, 2H), 4.44, 4.42 (s,2H), 3.19 (m, bs, 4H), 2.88 (m, 4H), 2.20 (s, 3H), 1.65 (bs, 6H),mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-hydroxy-benzylamino)-4-(4-methyl-piperazin-1-yl)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=4-hydroxy-benzylamino, R2=4-methyl-piperazin-1-yl], cpd. 99

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.05 (bs, 1H), 10.33, 10.28(s, 1H), 9.35, 9.30 (m, bs, 1H), 8.36 (m, 1H), 7.72-7.57 (m, 3H), 7.18(d, J=8.17 Hz, 2H), 6.75 (d, J=8.17 Hz, 2H), 6.69-6.03 (m, bs, 2H),4.55, 4.50 (bs, 2H), 4.28 (d, J=5.37 Hz, 2H), 3.21 (m, 4H), 2.40 (m,4H), 2.22 (s, 3H), 1.67, 1.62 (s, 6H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-hydroxy-benzylamino)-4-(4-methyl-piperazin-1-yl)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=2-hydroxy-benzylamino, R2=4-methyl-piperazin-1-yl], cpd. 101

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.40, 12.03 (bs, 1H), 10.29, 9.99(s, 1H), 9.59 (s, 1H), 8.40 (m, bs, 1H), 7.69-7.57 (m, 3H), 7.22 (d, bs,J=7.07 Hz, 1H), 7.09 (m, 1H), 6.85 (d, bs, J=7.93 Hz, 1H), 6.81-6.75 (m,1H), 6.36-6.10 (m, bs, 2H), 4.58-4.50 (bs, 2H), 4.32 (d, J=5.61 Hz, 2H),3.23 (m, bs, 4H), 2.41 (m, bs, 4H), 2.23, 2.20 (s, 3H), 1.65 (bs, 6H),mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-thiopyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=tetrahydro-thiopyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 97

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.35, 12.03 (s, 1H), 10.26 (s, 1H),8.17 (m, 1H), 7.66-7.50 (m, 4H), 6.26-6.09 (m, 1H), 6.04 (m, 1H),4.54-4.42 (m, 2H), 3.57 (m, 1H), 3.21 (m, 4H), 2.72-2.62 (m (m, 4H),2.38 (m, 4H), 2.18 (s, 3H), 2.12 (m, 2H), 1.66-1.48 (m, 8H), mixture oftautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino]-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino,R2=4-methyl-piperazin-1-yl], cpd. 100

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.89 (d, J=8.80 Hz, 1H), 7.69-7.57(m, 3H), 6.88 (m, bs, 1H), 6.83 (d, bs, J=8.80 Hz, 1H), 4.64 (s, 2H),4.56, 3.13-2.73 (m, bs, 9H), 2.67 (s, 3H), 2.45 (m, 4H), 2.24 (s, 3H),1.86-1.28 (m, bs, 10H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino]-4-morpholin-4-yl-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=((R)-1-methyl-pyrrolidin-2-ylmethyl)-amino, R2=morpholin-4-yl], cpd.87

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 7.90 (d, J=8.90 Hz, 1H), 7.69-7.58(m, 3H), 6.90 (m, bs, 1H), 6.85 (d, bs, J=8.90 Hz, 1H), 4.64 (s, 2H),3.75 (m, 4H), 3.20-2.87 (m, bs, 7H), 2.78 (m, bs, 2H), 2.68 (s, 3H),1.83 (m, bs, 1H), 1.70-1.56 (m, bs, 8H), 1.31 (m, bs, 1H).

N-[5-(2-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=2-fluorophenyl,R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 109

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.38, 12.06 (2s, 1H), 10.35, 10.30(2s, 1H), 8.15 (m, 1H), 7.91 (m, 1H), 7.78-7.54 (m, 2H), 7.52-7.38 (m,2H), 6.33-6.07 (m, 2H), 4.64-4.59 (2s, 2H), 3.84 (m, 2H), 3.70 (m, 1H),3.52 (m, 2H), 3.27 (m, 4H), 2.45 (m, 4H), 2.24 (s, 3H), 1.96m (m, 2H),1.61, 1.55 (2s, 6H), 1.40 (m, 2H), mixture of tautomers.

N-[5-(3,5-Dichloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-dichlorophenyl,R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 110

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.35 (bs, 1H), 10.41 (bs, 1H), 8.21(m, 1H), 8.01 (m, 1H), 7.86 (m, 2H), 7.73-7.66 (m, 1H), 6.28 (m, 1H),6.20 (m, 1H), 4.52 (bs, 2H), 4.08-3.99 (m, 2H), 3.89-3.82 (m, 2H), 3.73(m, 1H), 3.52 (m, 4H), 3.2-3.0 (m, 4H), 2.88 (bs, 3H), 1.97 (m, 2H),1.66 (s, 6H), 1.41 (m, 2H).

N-[5-(3-Chloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3-chlorophenyl,R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 111

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.06 (2bs, 1H), 10.30 (bs,1H), 8.15 (m, 1H), 7.90-7.85 (m, 2H), 7.78 (m, 1H), 7.66 (m, 2H),6.31-6.15 (m, 1H), 6.12 (m, 1H), 4.51, 4.45 (2bs, 2H), 3.84 (m, 2H),3.69 (m, 1H), 3.52 (m, 2H), 3.27 (m, 4H), 2.45 (m, 4H), 2.25 (bs, 3H),1.96 (m, 2H), 1.67, 1.63 (2bs, 6H), 1.40 (m, 2H), mixture of tautomers.

N-[5-(2,6-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=2,6-difluorophenyl,R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 113

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.06 (2bs, 1H), 10.37, 10.32(2bs, 1H), 8.15 (m, 1H), 7.78-7.55 (m, 1H), 7.32 (m, 1H), 7.66 (m, 2H),6.31-6.15 (m, 1H), 6.13 (m, 1H), 4.69, 4.64 (2bs, 2H), 3.84 (m, 2H),3.71 (m, 1H), 3.52 (m, 2H), 3.28 (m, 4H), 2.45 (m, 4H), 2.24 (s, 3H),1.96 (m, 2H), 1.62, 1.59 (2bs, 6H), 1.39 (m, 2H), mixture of tautomers.

N-[6,6-Dimethyl-5-(thiophene-2-sulfonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=thiophen-2-yl,R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 112

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.06 (2bs, 1H), 10.32 (bs,1H), 8.13 (m, 1H), 7.97 (m, 1H), 7.75-7.54 (m, 2H), 7.21 (m, 1H),6.32-6.09 (m, 2H), 4.51 (m, 2H), 3.84 (m, 2H), 3.70 (m, 1H), 3.52 (m,2H), 3.32 (m, 4H), 2.45 (m, 4H), 2.24 (s, 3H), 1.96 (m, 2H), 1.66 (bs,6H), 1.40 (m, 2H), mixture of tautomers.

N-[5-(3-Methoxy-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3-methoxyphenyl,R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 115

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.36, 12.04 (2bs, 1H), 10.20 (bs,1H), 8.14 (m, 1H), 7.70-7.43 (m, 3H), 7.33 (m, 1H), 7.25 (m, 1H),6.31-6.15 (m, 1H), 6.12 (m, 1H), 4.48, 4.41 (2bs, 2H), 3.88-3.80 (m,5H), 3.70 (m, 1H), 3.52 (m, 2H), 3.27 (m, 4H), 2.44 (m, 4H), 2.24 (s,3H), 1.96 (m, 2H), 1.69, 1.63 (2bs, 6H), 1.39 (m, 2H), mixture oftautomers.

N-[6,6-Dimethyl-5-(pyridine-3-sulfonyl)-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=pyridin-3-yl,R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 114

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.39, 12.06 (2bs, 1H), 10.30 (bs,1H), 9.05 (m, 1H), 8.85 (m, 1H), 8.31 (m, 1H), 8.11 (m, 1H), 7.71-7.52(m, 2H), 6.32-6.15 (m, 1H), 6.12 (m, 1H), 4.54, 4.48 (2bs, 2H), 3.85 (m,2H), 3.69 (m, 1H), 3.52 (m, 2H), 3.27 (m, 4H), 2.44 (m, 4H), 2.24 (s,3H), 1.96 (m, 2H), 1.66, 1.63 (2bs, 6H), 1.40 (m, 2H), mixture oftautomers.

N-[5-(3-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3-fluorophenyl,R1=tetrahydro-pyran-4-ylamino, R2=4-methyl-piperazin-1-yl], cpd. 104

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.43, 12.08 (2bs, 1H), 10.39, 10.34(2bs, 1H), 8.15 (m, 1H), 7.74 (m, 1H), 7.72-7.63 (m, 3H), 7.54 (m, 1H),6.25 (m, 1H), 6.18 (m, 1H), 4.48 (bs, 2H), 3.84 (m, 2H), 3.71 (m, 1H),3.51 (m, 2H), 3.50-3.35 (m, 8H), 2.83 (s, 3H), 1.94 (m, 2H), 1.63 (bs,6H), 1.39 (m, 2H), mixture of tautomers.

Example 17 Preparation ofN-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(piperidin-3-ylmethyl)-amino]-benzamide[(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=(piperidin-3-ylmethyl)-amino], cpd. 88

To a solution of2-amino-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide(100 mg, 0.223 mmol) in N,N-dimethylformamide (2.5 mL) were added sodiumtriacetoxyborohydride (240 mg, 1.12 mmol, 5 eq),3-formyl-piperidine-1-carboxylic acid tert-butyl ester (145 mg, 0.67mmol, 3 eq) and trifluoroacetic acid (0.25 mL). The reaction mixture wasstirred at room temperature overnight, then 4N hydrochloric acid in1,4-dioxane (5 mL) and dichloromethane (5 mL) were added, the mixturestirred for additional 5 hours, concentrated under vacuum, basified with2N NaOH, extracted with dichloromethane and dried over sodium sulfate.After evaporation of the solvent, the crude was purified by flashchromatography on silica gel using dichloromethane-methanol-30% NH₄OH100:10:1 as eluant, affording the title compound as white solid (42 mg).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.43 (bs, 1H), 12.72 (bs, 1H),7.76-7.71 (m, 2H), 7.66 (m, 1H), 7.60 (m, 2H), 7.35 (m, 1H), 6.78 (d,bs, J=8.90 Hz, 1H), 6.61 (m, 1H), 4.58 (bs, 2H), 3.22-3.05 (m, 6H), 2.66(m, 1H), 1.92-1.19 (m, bs, 10H).

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[((S)-1-pyrrolidin-2-ylmethyl)-amino]-benzamidehydrochloride [(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=((S)-1-pyrrolidin-2-ylmethyl)-amino], cpd. 76

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.80 (s, 1H), 9.12 (bs, 1H), 8.67(bs, 1H), 7.74 (dd, J1=7.92 Hz, J2=1.47 Hz, 1H), 7.67 (m, 1H), 7.61 (m,2H), 7.38 (ddd, J1=8.90 Hz, J2=7.08 Hz, J2=1.47 Hz, 1H), 6.88 (d, J=8.90Hz, 1H), 6.69 (dd, bs, J1=7.92 Hz, J2=7.08 Hz, 1H), 4.61 (s, 2H), 3.74(m, 1H), 3.52 (m, 2H), 3.21 (m, 2H), 2.13 (m, 1H), 2.03-1.83 (m, 2H),1.67 (m, 7H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-[(((R)-1-pyrrolidin-2-ylmethyl)-amino]-benzamidehydrochloride [(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=((R)-1-pyrrolidin-2-ylmethyl)-amino, R2=morpholin-4-yl], cpd. 77

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.46 (s, 1H), 9.19 (bs, 1H), 8.69(bs, 1H), 7.71 (d, J1=9.02 Hz, 1H), 7.66 (m, 1H), 7.60 (m, 2H), 6.30(dd, J1=9.02 Hz, J2=1.95 Hz, 1H), 6.15 (d, J2=1.95 Hz, 1H), 4.58 (s,2H), 3.75 (m, 4H), 3.58-3.30 (m, 5H), 3.27 (m, 4H), 2.12 (m, 1H),2.02-1.84 (m, 2H), 1.72-1.66 (m, 7H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((R)-1-pyrrolidin-2-ylmethyl)-amino]-benzamidedihydrochloride [(I) Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=((R)-pyrrolidin-2-ylmethyl)-amino,R2=4-methyl-piperazin-1-yl], cpd. 91

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.75 (bs, 1H), 10.52 (bs, 1H), 8.27(bs, NH₂ ⁺), 7.73 (d, J1=9.03 Hz, 1H), 7.66 (m, 1H), 7.60 (m, 2H), 6.34(dd, J1=9.03 Hz, J2=2.31 Hz, 1H), 6.23 (d, J2=2.31 Hz, 1H), 4.59 (s,2H), 4.09 (m, 2H), 3.77-3.08 (m, 11H), 2.84 (d, 3H), 2.17-1.61 (m, 4H),1.65 (s, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-[((S)-1-pyrrolidin-2-ylmethyl)-amino]-benzamidedihydrochloride [(I) Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=((S)-1-pyrrolidin-2-ylmethyl)-amino,R2=4-methyl-piperazin-1-yl], cpd. 92

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.75 (bs, 1H), 10.52 (bs, 1H), 8.27(bs, NH2+), 7.73 (d, J1=9.03 Hz, 1H), 7.66 (m, 1H), 7.60 (m, 2H), 6.34(dd, J1=9.03 Hz, J2=2.31 Hz, 1H), 6.23 (d, J2=2.31 Hz, 1H), 4.59 (s,2H), 4.09 (m, 2H), 3.77-3.08 (m, 11H), 2.84 (d, 3H), 2.17-1.61 (m, 4H),1.65 (s, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(piperidin-4-ylamino)-benzamidedihydrochloride [(I) Ra═Rb=methyl, A=D=E=CH, B=CR2,R=3,5-difluorophenyl, R1=piperidin-4-ylamino,R2=4-methyl-piperazin-1-yl], cpd. 98

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.79 (bs, 1H), 10.47 (s, 1H), 9.16(bs, 1H), 8.88 (bs, 1H), 8.55 (bs, 1H), 8.15 (bs, 1H), 7.70 (d, J1=9.07Hz, 1H), 7.63 (m, 1H), 7.58 (m, 2H), 6.29 (dd, bs, J1=9.07 Hz, J2=1.93Hz, 1H), 6.17 (d, bs, J2=1.93 Hz, 1H), 4.54 (s, 2H), 4.01 (m, 2H), 3.78(m, 1H), 3.49-3.01 (m, 10H), 2.81 (d, 3H), 2.56 (m, 2H), 2.10 (m, 2H),1.64-1.53 (m, 8H)

Example 18 Preparation ofN-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-ethyl-ureido)-4-(4-methyl-piperazin-1-yl)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=3-ethyl-ureido, R2=4-methyl-piperazin-1-yl], cpd. 127

To a solution of3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (308 mg, 0.5 mmol) in tetrahydrofuran (20 mL) ethylisocyanate (0.119 mL, 1.5 mmol, 3 eq) was added and the mixture stiffedat 50° C. for 24 hours. Additional ethyl isocyanate (1.2 mL) was thenadded, the mixture stirred at 50° C. for 4 days and then evaporated todryness. The residue was treated with 10 mL of methanol/triethylamine8:2, stirred at room temperature for 4 hours and evaporated to dryness.The crude was purified by flash chromatography on silica gel usingdichloromethane-methanol-30% NH₄OH 96:4:0.4 then 90:10:1 as eluantaffording the title compound as white solid (183 mg).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.48, 12.05 (2s, 1H), 10.65 (bs,1H), 10.25, 10.16 (bs, 1H), 8.00 (m, 1H), 7.75-7.60 (m, 4H), 7.22 (bs,1H), 6.66-6.47 (m, 1H), 4.65, 4.57 (2bs, 2H), 3.26 (m, 4H), 3.10 (m,2H), 2.46 (m, 4H), 2.24 (s, 3H), 1.68, 1.64 (2s, 6H), 1.08 (t, 3H),mixture of tautomers.

Example 19 Preparation of morpholine-4-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(morpholine-4-carbonyl)-amino, R2=4-methyl-piperazin-1-yl], cpd. 130

A mixture of3-[2-Amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (308 mg, 0.5 mmol), N,N-diisopropylethylamine (0.104mL, 0.6 mmol, 1.2 eq), morpholine-4-carbonyl chloride (1.2 mL, 10 mmol,20 eq) and tetrahydrofuran (20 mL) was stirred at 60° C. for 7 days. Thereaction mixture was then poured into water (100 mL), extracted withdichloromethane (100 mL), dried over sodium sulfate and evaporated todryness. The crude was purified by flash chromatography on silica gel(acetone as eluant) affording 112 mg of5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-3-{4-(4-methyl-piperazin-1-yl)-2-[(morpholine-4-carbonyl)-amino]-benzoylamino}-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester that was treated with 10 mL of methanol/triethylamine8:2 and stirred at room temperature overnight. The mixture wasevaporated to dryness and the residue purified by flash chromatographyon silica gel using dichloromethane-methanol-30% NH₄OH 96:4:0.4 aseluant, yielding the title compound as white solid (50 mg).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.53, 12.23 (2s, 1H), 11.14, 11.25(2s, 1H), 10.78, 10.75 (2s, 1H), 8.05 (m, 1H), 7.88, 7.75 (2m, 1H), 7.67(m, 1H), 7.60 (m, 2H), 6.68, 6.59 (2m, 1H), 4.60, 4.52 (2s, 2H), 3.65(m, 4H), 3.45 (m, 4H), 3.28 (m, 4H), 2.46 (m, 4H), 2.24 (s, 3H), 1.68,1.65 (2s, 6H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3,3-dimethyl-ureido)-4-(4-methyl-piperazin-1-yl)-benzamide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=3,3-dimethyl-ureido, R2=4-methyl-piperazin-1-yl], cpd. 128

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.52, 12.17 (2s, 1H), 11.38, 11.17(2s, 1H), 10.75, 10.72 (2s, 1H), 8.11 (m, 1H), 7.89, 7.74 (2m, 1H), 7.67(m, 1H), 7.59 (m, 2H), 6.67, 6.57 (m, 1H), 4.56, 4.51 (2s, 2H), 3.28 (m,4H), 2.99 (s, 6H), 2.46 (m, 4H), 2.24 (s, 3H), 1.69, 1.65 (2s, 6H),mixture of tautomers.

Pyrrolidine-1-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide[(I) Ra═Rb=methyl, A=D=E=CH, B=CR2, R=3,5-difluorophenyl,R1=(pyrrolidine-1-carbonyl)-amino, R2=4-methyl-piperazin-1-yl], cpd. 129

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.52, 12.17 (2s, 1H), 11.17, 10.98(2s, 1H), 10.74, 10.72 (2s, 1H), 8.13 (m, 1H), 7.87, 7.74 (2m, 1H), 7.68(m, 1H), 7.58 (m, 2H), 6.65, 6.56 (2m, 1H), 4.58, 4.52 (2s, 2H), 3.40(m, 4H), 3.30 (m, 4H), 2.50 (m, 4H), 2.28 (bs, 3H), 1.93 (m, 4H), 1.69,1.65 (2s, 6H), mixture of tautomers.

Example 20 Preparation ofN-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-3-(tetrahydro-pyran-4-ylamino)-isonicotinamide[(I) Ra═Rb=methyl, A=D=E=CH, B=N, R=3,5-difluorophenyl,R1=tetrahydro-pyran-4-ylamino], cpd. 117

Step 1 Preparation of 3-(tetrahydro-pyran-4-ylamino)-isonicotinic acidmethyl ester

To a mixture of 3-amino-isonicotinic acid methyl ester (500 mg, 3.29mmol), dry N,N-dimethylformamide (10 mL), trifluoroacetic acid (1 mL)and sodium triacetoxyborohydride (1.4 g, 6.6 mmol, 2 eq) was addedtetrahydro-pyran-4-one (0.5 mL, 4.94 mmol, 1.3 eq). The reaction mixturewas stirred at room temperature for 24 hours then poured into saturatedsodium hydrogenocarbonate (100 mL) and extracted with ethyl acetate (100mL). The organic layer was dried over sodium sulfate and evaporated todryness affording the crude title compound as yellow syrup that was usedas such for the next step.

Step 2 Preparation of3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-isonicotinicacid

The crude 3-(tetrahydro-pyran-4-ylamino)-isonicotinic acid methyl ester(3.29 mmol) was treated with 0.5 N sodium hydroxide (6.6 mL, 3.3 mmol)and methanol (15 mL) and stirred at 75° C. for 2 hours. An additionalamount of 0.5 N sodium hydroxide (0.4 mL) was then added and thestirring continued for 2 hours at 75° C. Hydrochloric acid (0.5 N) wasthen added until acidic pH and the mixture evaporated to dryness. Theresidue was then suspended in trifluoroacetic anhydride (5 mL) anddichloromethane (5 mL), stirred at room temperature for 1 h, evaporatedto dryness, treated with water (10 mL) and stirred at room temperaturefor 30 minutes. The precipitated material was filtered, washed withwater then with diethyl ether and dried affording the title compound aswhite solid (829 mg).

1H-NMR (400 MHz), 6: (ppm, DMSO-d₆): 8.88 (d, J=5.0 Hz, 1H), 8.77 (s,1H), 7.94 (d, J=5.0 Hz, 1H), 4.57 (m, 1H), 3.84 (m, 2H), 3.41 (m, 2H),1.95 (m, 1H), 1.60 (m, 1H), 1.47 (m, 1H), 1.08 (m, 1H).

Step 3 Preparation of3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-isonicotinoylchloride

To a suspension of3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-isonicotinicacid (350 mg, 1.1 mmol) in dry dichloromethane (15 mL) and oxalylchloride (0.65 mL, 6.6 mmol, 6 eq) a drop of N,N-dimethylformamide wasadded. The mixture was stirred at room temperature for 1 h and thenevaporated to dryness affording the crude title compound that was usedas such for the next step.

Step 4 Preparation of3-({3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-pyridine-4-carbonyl}-amino)-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylicacid 5-tert-butyl ester 1-ethyl ester [(IV) Q=Ethyl, Ra═Rb=methyl,A=D=E=CH, B=N,R1=(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]

To a mixture of3-amino-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylic acid5-tert-butyl ester 1-ethyl ester (244 mg, 0.75 mmol), drytetrahydrofuran (30 mL) and N,N-diisopropylethylamine (0.75 mL, 4.4mmol) was added3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]isonicotinoylchloride (1.1 mmol). The mixture was stirred at 45° C. for 1 h, thenevaporated to dryness, diluted with dichloromethane (100 mL), washedwith saturated sodium hydrogenocarbonate (100 mL), dried over sodiumsulfate and evaporated to dryness affording the crude title compoundthat was used as such for the next step.

Step 5 Preparation of3-({3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-pyridine-4-carbonyl}-amino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester hydrochloride [(V) Q=Ethyl, Ra═Rb=methyl,A=D=E=CH, B=N,R1=(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]

A mixture of3-({3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-pyridine-4-carbonyl}-amino)-4,6-dihydro-pyrrolo[3,4-c]pyrazole-1,5-dicarboxylicacid 5-tert-butyl ester 1-ethyl ester (0.75 mmol), dichloromethane (20mL) and 4N hydrochloric acid in 1,4-dioxane (3 mL) was stiffed at roomtemperature overnight and then evaporated to dryness. The residue wasstirred with diethyl ether, filtered, and dried affording the crudetitle compound that was used as such for the next step.

Step 6 Preparation ofN-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-3-(tetrahydro-pyran-4-ylamino)-isonicotinamide[(I) Ra═Rb=methyl, A=D=E=CH, B=N, R=3,5-difluorophenyl,R1=tetrahydro-pyran-4-ylamino], cpd. 117

To a mixture of3-({3-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-pyridine-4-carbonyl}-amino)-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylicacid ethyl ester hydrochloride (0.75 mmol), dry dichloromethane (50 mL)and triethylamine (0.84 mL, 6 mmol) was added3,5-difluorobenzenesulfonyl chloride (478 mg, 2.25 mmol). The mixturewas stirred at room temperature for 4 hours then methanol (10 mL) andtriethylamine (5 mL) were added. The mixture was then heated to 60° C.and the stiffing continued for 2 hours. The solvents were evaporated andthe crude residue purified by flash chromatography on silica gel,affording the title compound as pale yellow solid (100 mg).

1H-NMR (400 MHz),

(ppm, DMSO-d₆): 12.59, 12.35 (2s, 1H), 11.04, 11.02 (2s, 1H), 8.87, 8.82(2s, 1H), 7.93, 7.86 (2m, 1H), 7.71-7.52 (m, 4H), 7.28 (d, 1H), 4.61,4.52 (2s, 2H), 3.86 (m, 2H), 3.81 (m, 1H), 3.50 (m, 2H), 1.98 (m, 2H),1.68, 1.64 (2s, 6H), 1.44 (m, 2H), mixture of tautomers.

Operating in an analogous way, the following compounds were obtained:

3-(Tetrahydro-pyran-4-ylamino)-pyridine-2-carboxylic acid[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-amide[(I) Ra═Rb=methyl, A=B=D=CH, E=N, R=3,5-difluorophenyl,R1=tetrahydro-pyran-4-ylamino], cpd. 121

1H-NMR (400 MHz), 6. (ppm, DMSO-d₆): 12.57, 12.14 (2s, 1H), 11.11, 10.35(2s, 1H), 8.19 (d, J=7.8 Hz, 1H), 7.90 (m, 1H), 7.69-7.59 (m, 3H),7.47-7.40 (m, 2H), 4.70, 4.65 (2s, 2H), 3.89 (m, 2H), 3.73 (m, 1H), 3.50(m, 2H), 1.97 (m, 2H), 1.67, 1.62 (2s, 6H), 1.47 (m, 2H), mixture oftautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-hydroxy-cyclohexylamino)-nicotinamide[(I) Ra═Rb=methyl, A=N, B=D=E=CH, R=3,5-difluorophenyl,R1=4-hydroxy-cyclohexylamino], cpd. 118

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.53, (bs, 1H), 10.84 (bs, 1H),8.21 (m, 1H), 8.12-7.98 (m, 2H), 7.70-7.59 (m, 3H), 6.58 (m, 1H), 4.57(m, 3H), 3.90 (m, 1H), 3.49 (m, 1H), 2.00 (m, 2H), 1.84 (m, 2H), 1.64(s, 6H), 1.28 (m, 4H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(tetrahydro-furan-2-ylmethyl)-amino]-nicotinamide[(I) Ra═Rb=methyl, A=N, B=D=E=CH, R=3,5-difluorophenyl,R1=(tetrahydro-furan-2-ylmethyl)-amino], cpd. 149

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.54, 12.22 (2bs, 1H), 10.86 (bs,1H), 8.31-7.97 (m, 3H), 7.64 (m, 1H), 7.59 (m, 2H), 6.58 (m, 1H),4.61-4.44 (m, 2H), 4.02 (m, 1H), 3.81 (m, 1H), 3.67 (m, 1H), 3.58 (m,1H), 3.43 (m, 1H), 2.00-1.77 (m, 3H), 1.67 (bs, 6H), 1.56 (m, 1H),mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(3-hydroxy-propylamino)-nicotinamide[(I) Ra═Rb=methyl, A=N, B=D=E=CH, R=3,5-difluorophenyl,R1=3-hydroxy-propylamino], cpd. 150

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.53, 12.25 (2bs, 1H), 10.84 (bs,1H), 8.27-7.98 (m, 3H), 7.69-7.58 (m, 3H), 6.67-6.52 (m, 1H), 4.66-4.46(m, 3H), 3.50 (m, 4H), 1.75-1.60 (m, 8H), mixture of tautomers.

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(4-methoxy-benzylamino)-nicotinamide[(I) Ra═Rb=methyl, A=N, B=D=E=CH, R=3,5-difluorophenyl,R1=4-methoxy-benzylamino], cpd. 151

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 12.52, 12.25 (2bs, 1H), 10.87 (bs,1H), 8.42-8.00 (m, 3H), 7.67-7.55 (m, 3H), 7.26 (m, 2H), 6.87 (m, 2H),6.74-6.52 (m, 1H), 4.63-4.46 (m, 4H), 3.72 (s, 3H), 1.65 (bs, 6H),mixture of tautomers.

Example 21 Preparation ofN-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(isopropylamino-methyl)-benzamidehydrochloride [(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=isopropylamino-methyl], cpd. 139

Step 1 Preparation of2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoic acid

To a solution of 3H-isobenzofuran-1-one (18 g, 134 mmol) in dryN,N-dimethylformamide (110 mL) was added potassium phthalimide (27 g,145 mmol). The mixture was stirred at reflux for 6 hours then cooled to0° C. and treated with 1N hydrochloric acid (180 mL). The yellow solidthus formed was filtered, washed with water, with ethanol and dried inoven. Crystallization with ethanol afforded the title compound as whitesolid (27 g).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 13.21 (bs, 1H), 7.97-7.86 (m, 5H),7.50 (m, 1H), 7.40 (m, 1H), 7.17 (m, 1H), 5.17 (s, 2H).

Step 2 Preparation of3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylicacid 5-tert-butyl ester 2-ethyl ester

To a suspension of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoicacid (1.35 g, 4.8 mmol) in dry dichloromethane (30 mL), at 0° C., understirring, was added oxalyl chloride (2.1 mL, 24 mmol) and dryN,N-dimethylformamide (35 microL). The mixture was allowed to warm toroom temperature, stirred for 1.5 hours then evaporated to dryness. Theresidue was diluted with dry toluene and evaporated again. The crudeacyl chloride thus obtained (yellow solid) was dissolved in drytetrahydrofuran (20 mL) and treated with N,N-diisopropylethylamine (2.5mL, 15 mmol) and with a solution of3-amino-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylic acid5-tert-butyl ester 2-ethyl ester (1.3 g, 4 mmol) in 15 mL of drytetrahydrofuran. The mixture was stirred at room temperature for 2 daysthen evaporated to dryness. The residue was dissolved indichloromethane, washed with 1N HCl, water, saturated solution ofNaHCO₃, brine, dried over sodium sulfate and evaporated to dryness. Thecrude was purified by flash chromatography on silica gel usingdichloromethane/methanol 98.5:1.5 as the eluant affording the titlecompound as white solid (1.5 g).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.63 (bs, 1H), 7.91-7.83 (m, 4H),7.71 (m, 1H), 7.58-7.46 (m, 2H), 7.37 (m, 1H), 5.07 (s, 2H), 4.53 (bs,2H), 4.43 (m, 2H), 1.63 (bs, 6H), 1.50 (s, 9H), 1.37 (m, 3H).

Step 3 Preparation of3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester hydrochloride

To a suspension of3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-4H,6H-pyrrolo[3,4-c]pyrazole-2,5-dicarboxylicacid 5-tert-butyl ester 2-ethyl ester (1.5 g, 2.5 mmol) in 1,4-dioxane(20 mL) was added 4N HCl in 1,4-dioxane (14 mL, 56 mmol). After stirringat room temperature overnight the volatiles were removed under reducedpressure and the residue triturated with diethylether affording thetitle compound as white solid (1.24 g).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.75 (bs, 1H), 9.89 (bs, 2H),7.91-7.83 (m, 4H), 7.72 (m, 1H), 7.58-7.46 (m, 2H), 7.37 (m, 1H), 5.07(s, 2H), 4.61 (bs, 2H), 4.45 (q, J=7.1 Hz, 2H), 1.69 (s, 6H), 1.36 (t,J=7.1 Hz, 3H).

Step 4 Preparation of5-(3,5-difluoro-benzenesulfonyl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester

To a suspension of3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester hydrochloride (1.24 g, 2.4 mmol) in dry dichloromethane(30 mL) was added N,N-diisopropylethylamine (1.67 mL, 9.6 mmol) and3,5-difluorobenzenesulfonyl chloride (0.77 g, 3.6 mmol). After stirringat room temperature for 3 hours the mixture was diluted withdichloromethane (50 mL), washed with 1N HCl, water, saturated solutionof NaHCO₃, brine, dried over sodium sulfate and evaporated to dryness.The crude was purified by flash chromatography on silica gel elutingwith ethyl acetate and then with dichloromethane/methanol 98:2 affordingthe title compound as white solid (1.4 g).

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 10.61 (bs, 1H), 7.83 (m, 4H),7.69-7.63 (m, 4H), 7.56-7.45 (m, 2H), 7.39 (m, 1H), 5.05 (s, 2H), 4.72(bs, 2H), 4.41 (q, J=7.1 Hz, 2H), 1.67 (s, 6H), 1.34 (t, J=7.1 Hz, 3H).

Step 5 Preparation of2-aminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide

To a suspension of5-(3,5-difluoro-benzenesulfonyl)-3-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoylamino]-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylicacid ethyl ester (0.23 g, 0.34 mmol) in methanol (15 mL) anddichloromethane (1.5 mL) was added hydrazine hydrate (50 microL, 1.02mmol). After stirring at reflux for 1 hour the volatiles were removedunder reduced pressure and the residue purified by flash chromatographyon silica gel eluting with dichloromethane/methanol/7N NH₃ in methanol95:4:1 affording the title compound as colorless oil (93 mg).

ESI (+) MS: m/z 462 (MH⁺).

Step 6 Preparation ofN-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(isopropylamino-methyl)-benzamidehydrochloride [(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=isopropylamino-methyl], cpd. 139

To a solution of2-aminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamide(93 mg, 0.2 mmol) in dichloromethane (6 mL) was added acetone (22microL, 0.3 mmol), sodium triacetoxyborohydride (59 mg, 0.28 mmol) andacetic acid (171 microL, 3 mmol). After stirring for 3.5 hours at roomtemperature the mixture was treated with 1M NaOH (3 mL). The organiclayer was separated, washed with brine, dried over sodium sulfate andevaporated to dryness. The residue was purified by flash chromatographyon silica gel eluting with dichloromethane/methanol/7N NH₃ in methanol95:4:1. The oil thus obtained was dissolved in dichloromethane (2 mL)and added with 2N HCl in Et₂O (0.4 mL). Evaporation of the volatilesafforded 56 mg of the title compound as white solid.

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.33 (bs, 1H), 8.61 (bs, 2H), 7.82(m, 1H), 7.72-7.51 (m, 6H), 4.61 (s, 2H), 4.23 (m, 2H), 3.43 (m, 1H),1.69 (s, 6H), 1.33 (d, J=6.5 Hz, 6H).

Operating in an analogous way, the following compounds were obtained:

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-[(tetrahydro-pyran-4-ylamino)-methyl]-benzamidehydrochloride [(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=[(tetrahydro-pyran-4-ylamino)-methyl], cpd. 141

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.36 (bs, 1H), 8.82 (bs, 2H), 7.83(m, 1H), 7.73-7.52 (m, 6H), 4.68 (s, 2H), 4.30 (m, 2H), 3.97 (m, 2H),3.50-3.30 (m, 3H), 2.06 (m, 2H), 1.73 (m, 2H), 1.69 (s, 6H).

2-Cyclobutylaminomethyl-N-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-benzamidehydrochloride [(I) Ra═Rb=methyl, A=B=D=E=CH, R=3,5-difluorophenyl,R1=cyclobutylaminomethyl], cpd. 142

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.30 (bs, 1H), 8.96 (bs, 2H), 7.82(m, 1H), 7.75-7.53 (m, 6H), 4.65 (s, 2H), 4.14 (m, 2H), 3.37 (m, 1H),2.35-2.16 (m, 4H), 1.85 (m, 2H), 1.70 (s, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-[(tetrahydro-pyran-4-ylamino)-methyl]-benzamidehydrochloride [(I) Ra═Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl,R1=[(tetrahydro-pyran-4-ylamino)-methyl, R2=fluoro], cpd. 135

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.44 (bs, 1H), 8.96 (bs, 2H),7.74-7.35 (m, 7H), 4.67 (s, 2H), 4.20 (m, 2H), 3.91 (m, 2H), 3.50-3.30(m, 3H), 2.00 (m, 2H), 1.68 (s, 6H), 1.63 (m, 2H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-(isopropylamino-methyl)-benzamidehydrochloride [(I) Ra═Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl,R1=isopropylamino-methyl, R2=fluoro], cpd. 133

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.45 (bs, 1H), 8.76 (bs, 2H),7.73-7.39 (m, 7H), 4.63 (s, 2H), 4.16 (m, 2H), 3.40 (m, 1H), 1.71 (s,6H), 1.31 (d, J=6.6 Hz, 6H).

N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-fluoro-6-morpholin-4-ylmethyl-benzamidehydrochloride [(I) Ra═Rb=methyl, A=B=D=CH, E=CR2, R=3,5-difluorophenyl,R1=morpholin-4-ylmethyl, R2=fluoro], cpd. 137

1H-NMR (400 MHz), δ (ppm, DMSO-d₆): 11.42 (bs, 1H), 10.36 (bs, 1H),7.72-7.57 (m, 5H), 7.45 (m, 1H), 4.64 (s, 2H), 4.37 (bs, 2H), 4.02-3.72(m, 4H), 3.4-3.1 (m, 4H), 1.69 (s, 6H).

The invention claimed is:
 1. A method for treating a disease caused byand/or associated with a dysregulated protein kinase activity whichcomprises administering to a mammal in need thereof an effective amountof a compound of formula (I) as defined

wherein: R is an optionally further substituted straight or branchedC₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl or aryl; R1 is selectedfrom NHCOR4, NHSO₂R10, NR5R6, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkylwherein: R4 is selected from an optionally further substitutedheterocycloalkyl, aryl, NR8R9, and R7O—C₁-C₆ alkyl; R5 is hydrogen, anoptionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, heterocycloalkyl, aryl, R8R9N—C₂-C₆ alkyl, and R7O —C₂-C₆alkyl, R6, is an optionally further substituted straight or branchedC₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl, aryl, R8R9N—C₂-C₆ alkyland R7O—C₂-C₆ alkyl; R7 is selected from hydrogen, an optionally furthersubstituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,heterocycloalkyl, aryl and R8R9N—C₂-C₆ alkyl; R8 and R9, being the sameor different, are independently selected from hydrogen, an optionallyfurther substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,heterocycloalkyl and aryl, or R8 and R9, taken together with thenitrogen atom to which they are bonded, form an optionally substitutedheterocycloalkyl group; R10 is an optionally further substitutedstraight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl oraryl; A, B, D and E represent a nitrogen atom, CH, CR2 or CR3, with amaximum of two of A, B, D and E representing a nitrogen atom, and with amaximum of two of A, B, D and E representing CR2 or CR3, wherein: R2 andR3, being the same or different, are independently selected fromhalogen, trifluoromethyl, nitro, OR7, NR8R9, an optionally furthersubstituted straight or branched C₁-C₆ alkyl, R8R9N—C₁-C₆ alkyl andR7O—C₁-C₆ alkyl, wherein R7, R8, and R9 are as defined above; Ra and Rb,being the same or different, are selected from hydrogen or methyl, withthe proviso that: when A, D and E are CH, and B is CR2, wherein R2 is4-methylpiperazine or morpholine, then R1 is not NHCOR4 wherein R4 ispyrrolidin-2-yl; or isomers, tautomers, carriers and pharmaceuticallyacceptable salt thereof, wherein the disease is selected from the groupconsisting of bladder cancer, blood cancer, bone cancer, brain cancer,breast cancer, cervical cancer, colon cancer, lung cancer, mesotheliumcancer, ovarian cancer, pancreatic cancer, prostate cancer and skincancer.
 2. The method according to claim 1 which provides tumorangiogenesis and metastasis inhibition.
 3. The method according to claim1 further comprising subjecting the mammal in need thereof to aradiation therapy or chemotherapy regimen in combination with at leastone cytostatic or cytotoxic agent.
 4. The method according to claim 1wherein the mammal in need thereof is a human.
 5. A method forinhibiting IGF1-R activity which comprises contacting the said receptorwith an effective amount of a compound of the formula

wherein: R is an optionally further substituted straight or branchedC₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl or aryl; R1 is selectedfrom NHCOR4, NHSO₂R10, NR5R6, R8R9N—C₁-C₆ alkyl and R7O—C₁-C₆ alkylwherein: R4 is selected from an optionally further substitutedheterocycloalkyl, aryl, NR8R9, and R7O—C₁-C₆ alkyl; R5 is hydrogen, anoptionally further substituted straight or branched C₁-C₆ alkyl, C₃-C₆cycloalkyl, heterocycloalkyl, aryl, R8R9N—C₂-C₆ alkyl, and R7O—C₂-C₆alkyl, R6, is an optionally further substituted straight or branchedC₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl, aryl, R8R9N—C₂-C₆ alkyland R7O—C₂-C₆ alkyl; R7 is selected from hydrogen, an optionally furthersubstituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,heterocycloalkyl, aryl and R8R9N—C₂-C₆ alkyl; R8 and R9, being the sameor different, are independently selected from hydrogen, an optionallyfurther substituted straight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl,heterocycloalkyl and aryl, or R8 and R9, taken together with thenitrogen atom to which they are bonded, form an optionally substitutedheterocycloalkyl group; R10 is an optionally further substitutedstraight or branched C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl oraryl; A, B, D and E represent a nitrogen atom, CH, CR2 or CR3, with amaximum of two of A, B, D and E representing a nitrogen atom, and with amaximum of two of A, B, D and E representing CR2 or CR3, wherein: R2 andR3, being the same or different, are independently selected fromhalogen, trifluoromethyl, nitro, OR7, NR8R9, an optionally furthersubstituted straight or branched C₁-C₆ alkyl, R8R9N—C₁-C₆ alkyl andR7O—C₁-C₆ alkyl, wherein R7, R8, and R9 are as defined above; Ra and Rb,being the same or different, are selected from hydrogen or methyl, withthe proviso that: when A, D and E are CH, and B is CR2, wherein R2 is4-methylpiperazine or morpholine, then R1 is not NHCOR4 wherein R4 is orpyrrolidin-2-yl; or isomers, tautomers, carriers and pharmaceuticallyacceptable salt thereof.
 6. The method of claim 1 wherein R is selectedfrom C₃-C₆ cycloalkyl, heterocycloalkyl and aryl; R1 is selected fromNHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl; A and D are CH or nitrogen, B isnitrogen, CH or CR2, and E is CH or CR3; R2 and R3 are independentlyselected from halogen, trifluoromethyl, OR7, NR8R9, R8R9N—C₁-C₆ alkyland R7O—C₁-C₆ alkyl.
 7. The method of claim 6 wherein R1 is selectedfrom NHCOR4, NR5R6, R8R9N—C₁-C₆ alkyl, and R7O—C₁-C₆ alkyl; A is CH ornitrogen, B is nitrogen, CH or CR2, E is CH or CR3, and D is CH; R2 andR3 are independently selected from halogen, OR7, NR8R9, R8R9N—C₁-C₆alkyl and R7O—C₁-C₆ alkyl.
 8. The method of claim 1 wherein R isheterocycloalkyl or aryl; R1 is selected from NHCOR4, NR5R6, R8R9N—C₁-C₆alkyl; B is CH or CR2, E is CH or CR3, and A and D are CH; Ra and Rb aremethyl.
 9. The method of claim 1 wherein R is aryl; B and E are CH, CR2or CR3, and A and D are CH.
 10. The method of claim 1 wherein B is CR2,and A, D and E are CH; R2 is selected from OR7, NR8R9, R8R9N—C₁-C₆ alkyland R7O—C₁-C₆ alkyl.
 11. The method of claim 1 wherein the compound isselected from the group consisting of: (S)-Tetrahydro-furan-2-carboxylicacid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;Tetrahydro-pyran-4-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;1H-Pyrrole-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;1H-Pyrrole-3-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;1-Methyl-1H-pyrrole-2-carboxylic acid[2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-(4-methyl-piperazin-1-yl)-phenyl]-amide;1H-Pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;1H-Pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;1H-Pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide;1H-Pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-methoxy-phenyl}-amide;1H-Pyrrole-3-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-phenyl}-amide;1H-Pyrrole-3-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;1-Methyl-1H-pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide;Tetrahydro-pyran-4-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-dimethylamino-phenyl}-amide;Tetrahydro-pyran-4-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-5-morpholin-4-yl-phenyl}-amide;N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-dimethylamino-2-(tetrahydro-pyran-4-ylamino)-benzamide;N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-morpholin-4-yl-2-(tetrahydro-pyran-4-ylamino)-benzamide;N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;1H-Pyrrole-2-carboxylic acid{2-[5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-ylcarbamoyl]-3-fluoro-phenyl}-amide;N-[5-(3-Chloro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;N-[5-(3-Fluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide;N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((R)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamide;N-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-((S)-2-methoxy-1-methyl-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamideandN-[5-(3,5-Difluoro-benzenesulfonyl)-6,6-dimethyl-1,4,5,6-tetrahydro-pyrrolo[3,4-c]pyrazol-3-yl]-2-(2-methoxy-ethylamino)-4-(4-methyl-piperazin-1-yl)-benzamideor pharmaceutically acceptable salt thereof.